Chemical signaling involved in plant–microbe interactions

Fernanda Oliveira Chagas , Rita de Cassia Pessotti , Andrés Mauricio Caraballo-Rodríguez and Mônica Tallarico Pupo *
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (FCFRP-USP), Avenida do Café, s/n, 14040-903, Ribeirão Preto-SP, Brazil. E-mail:

Received 15th May 2017

First published on 8th December 2017

Microorganisms are found everywhere, and they are closely associated with plants. Because the establishment of any plant–microbe association involves chemical communication, understanding crosstalk processes is fundamental to defining the type of relationship. Although several metabolites from plants and microbes have been fully characterized, their roles in the chemical interplay between these partners are not well understood in most cases, and they require further investigation. In this review, we describe different plant–microbe associations from colonization to microbial establishment processes in plants along with future prospects, including agricultural benefits.

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Fernanda Oliveira Chagas

Fernanda O. Chagas received her PhD in Sciences (2014) from the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil, under the supervision of Prof. Mônica T. Pupo. During a doctoral internship (2011–2012), she spent one year at Prof. Eric W. Schmidt's laboratory, L. S. Skaggs Pharmacy Research Institute, University of Utah, United States. She completed her training as a postdoctoral researcher at Pupo's laboratory for two years (2014–2016), working on the chemistry and genetics of microorganisms. She received a MS in Sciences (2010) and a BS in Pharmacy-Biochemistry (2007) from the University of São Paulo. Currently she is an Assistant Professor of Natural Products at the Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro, Brazil. Her research interests include microbial interactions and their ecological roles, genetic manipulation and biosynthetic studies on microorganisms.

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Rita de Cassia Pessotti

Rita de Cassia Pessotti received her PhD in Sciences (2016) from the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil, under the supervision of Prof. Mônica T. Pupo. She did part of her doctoral training (2013–2014) at Prof. Roberto Kolter's laboratory, at Harvard Medical School, United States. She worked on biological and chemical aspects of interspecies interaction among endophytic actinobacteria, as well as genomics and isolation of natural products from rare actinobacteria from soil. She received a BS in Biology (2011) from the University of São Paulo, Brazil. Currently she is a postdoctoral researcher in the Department of Plant and Microbial Biology under Prof. Matthew F.Traxler's supervision at the University of California, Berkeley, United States. Her research interests include chemistry and genomics of natural products, and chemical ecology of symbiotic microbes and their hosts.

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Andrés Mauricio Caraballo-Rodríguez

Andrés Mauricio Caraballo Rodríguez earned his PhD (2017) from the Laboratory of Chemistry of Microorganisms (LQMo) under the supervision of Prof. Mônica T. Pupo, at the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil. During his PhD research, he spent one year at Prof. Pieter Dorrestein's Lab in the Skaggs School of Pharmacy and Pharmaceutical Sciences-UCSD, United States, applying recent mass spectrometry tools studying microbial interactions of endophytic microorganisms. He received a MS in Biosciences and Law (2011) and a BS in Pharmacy (2006) from Universidad Nacional de Colombia. His research interests include detection, characterization and the role of natural products in their natural environments.

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Mônica Tallarico Pupo

Mônica T. Pupo graduated with a BS in Pharmacy in 1990 from the University of São Paulo (USP), Ribeirão Preto campus, and then earned her PhD in Chemistry from Federal University of São Carlos in 1997. She was a postdoctoral researcher at the Physics Institute of São Carlos, USP, for one year and then she joined the School of Pharmaceutical Sciences of Ribeirão Preto, USP, in 1998 as an assistant professor. She was appointed associate professor in 2009. She was a visiting scholar at the Jon Clardy group, Harvard Medical School, Boston, USA, from 2006 to 2007. Her research interests include the chemistry, biology and ecology of natural products from microbial symbionts.

1. Introduction

Plants and microorganisms have an intimate evolutionary history together as established by their diverse interactions as symbionts.1–3 Fossil records of biotrophic fungi in close association with plants constitute a well-known case of symbiosis called mycorrhizal symbiosis, showing that the plant–microbe partnership dates back to the origin of land plants.4–6 It is hypothesized that the establishment of symbiosis between plants and mycorrhiza was an important mechanism to allow for plant terrestrialization by helping plants to cope with some of the constraints imposed by land colonization, such as nutrient and water uptake, exemplifying the important role of plant–microbial symbiosis over the course of evolution.4,5,7,8 The term “symbiosis” has been defined in many different ways. In this review, we use de Bary's definition, which comprises any intimate species interaction, either positive or negative, including mutualism, commensalism, and parasitism.9,10 Because pathogenic interactions can be considered a type of parasitism,9 plant–pathogen interactions will be discussed in this review as a case of symbiosis.

Microorganisms that interact positively with plants include rhizobia, mycorrhiza, endophytes (including plant growth-promoting microorganisms, or PGPMs) and epiphytes. These interactions afford plants some benefits, such as protection against biotic and abiotic stresses, growth promotion, and increased nutrient availability; plants also benefit microbes by providing protection and nutrients.11–18 However, microbial pathogens of plants are involved in negative interactions, causing disease and damaging their hosts.19–21 Additionally, the status of an ecological interaction between plants and microorganisms can vary. In some cases, microbes can shift from mutualist to commensalist to pathogen depending on the environmental, host developmental or intrinsic microbial conditions.22,23

Chemical cues are important for attracting microorganisms during the colonization of plants, the induction of plant defense mechanisms, pathogenesis and the establishment of mutualistic associations between symbiotic partners. Thus, all interactions involving plants and their associated microbes depend on appropriate chemical signaling, which can occur in a specific or generalized manner. Chemical signaling is also important during microbe–microbe interactions. Microorganisms can present a cooperative behavior, providing benefits for both individuals and the microbial community,24,25 as well as a competitive behavior.26,27 During both cooperation and competition, secondary metabolites or small molecules are involved by acting as mediators of microbe–microbe and plant–microbe interactions, which can also trigger plant responses.28 For a better understanding, we have adopted a broad definition of signaling in this review as an action that is equivalent to communication because cell–cell communication is mediated by molecules.28,29 Therefore, either chemical communication or chemical signaling terms will be used.

Global molecular communication between plants and microorganisms encompasses chemical signaling from plants to microorganisms, signaling from microbes to plants, and microbial intraspecies and interspecies signaling.27 In considering the complexity of these biological interactions, we address the chemical signaling involved in positive, neutral, and negative symbiotic relationships between plants and microorganisms. We discuss the importance of metabolites related to plant–microbe communication and provide some examples of the molecules that play important roles in those interactions.

2. The establishment of symbiosis: a process of microbial attraction and modulation of the host immunity

2.1. Plants attract symbiotic microorganisms

2.1.1. Rhizosphere microbes play a central role in the microbial colonization of plants. Root colonization is an important first step in both beneficial associations with microorganisms and infections by soil-borne pathogens.30 This process involves the attraction of rhizosphere microbes through compounds that are exuded by plants and the modulation of host immunity upon contact with these potential intruders.26,31 The plant initiates crosstalk with soil microbes through signals produced by both the host and the colonizers.30,32–35 These exchanges of chemical signals coordinate all the steps of plant–microbe interplay until the consolidation of symbiosis (Fig. 1). Furthermore, microbe–microbe signaling is intimately involved in each step of the root colonization process.36,37
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Fig. 1 Representative overview of the exudation process, microbial attraction and repulsion through chemical signaling in the rhizosphere, and the likely sources of microorganism-colonizing plants.

The majority of microorganisms that colonize plants are derived from the rhizosphere.34,38 The rhizosphere was first described by Hiltner as the volume of soil surrounding the roots that is affected by their presence.34,39,40 Pinton and collaborators redefined the term as the zone that includes the soil influenced by the root along with the root tissues that are colonized by microorganisms.34,41 The rhizosphere microbial community may change due to the intrinsic characteristics of the plants, including the plant genotype and developmental stage, immune system signaling and root exudation. In addition, significant effects on the composition of rhizosphere communities have been assigned to soil types and to the presence of antagonistic or mutualistic microorganisms in the rhizosphere.32,35,42–51

2.1.2. Plant exudates: their composition, effect on surrounding microorganisms and importance for symbiosis. The number and activity of microorganisms increase in the vicinity of plant roots because microorganisms are attracted to the nutrients that are exuded by roots. Root colonization is initiated at specific and distinct points of the roots, suggesting that these sites release abundant exudates.52,53 Once the rhizosphere microorganisms recognize the chemical signals contained in the exudates, the communication and interaction process begins.38 Chemical signaling plays important roles in the colonization process.

The production of root exudates represents a significant carbon cost to the plant, and it represents one of the major losses of photosynthetically fixed carbon along with the carbon that is taken up by associated microorganisms.30,54 The composition of root exudates is highly complex, making their detailed characterization difficult. Nevertheless, numerous components have been identified, some of which are common and others that are rather unique to certain plant species.53 These matrices of soluble compounds that are released into the soil are used by the microbial communities in the rhizosphere. Therefore, root exudates can be substrates for soil microbes and/or signaling molecules, acting as chemical attractants or even repellants of fungi, bacteria and other organisms (Fig. 1).30,54,55 The exuded compounds can also mediate tripartite interactions among the plant host, beneficial microorganisms and pathogens in the rhizosphere.56

The exudates are grouped into low- or high-molecular-weight compounds. Low-molecular-weight compounds comprise a high diversity of molecules, including sugars, amino acids, organic acids, phenolic compounds, and other secondary metabolites, while high-molecular-weight compounds, such as polysaccharides and proteins, are less diverse but often yield a larger proportion of root exudates by mass.30,33,35 Many compounds that are secreted by plant roots, such as carbohydrates and amino acids, act as general chemoattractants for a diversity of microbes, while others mediate more specific interactions.57–59 Plant hormones and other secondary metabolites attract beneficial soil microorganisms and can defend plants against pathogens.60 Proteins that have been released as root exudates are important for recognizing both pathogenic and non-pathogenic bacteria.61,62 Lectins are among the most frequently studied proteins, acting in both symbiotic interactions and in defense responses.63 Plants also secrete proteins with enzymatic activity that are involved in defense.64 The cells and mucilage (polysaccharides) released from plant root tips into the rhizosphere contain large amounts of arabinogalactan proteins, which participate in different interactions between plant roots and rhizosphere microbes. Arabinogalactan proteins are able to attract beneficial microorganisms to plants and repel pathogens.65–68 Additionally, plants produce compounds, such as the flavonoid rutin (1, Chart 8), that can attract and control mutualistic fungi while acting as non-specific signals that are also sensed by pathogenic microorganisms,69,70 exemplifying the complexity behind chemical signaling in plant–microbe symbioses.

The composition of root exudates is influenced by diverse factors, including the plant species and developmental stage, environmental factors, and the presence of microorganisms.31,71–73 Root exudation was first believed to occur through a passive process until the discovery that plants can actively secrete metabolites into the environment.31,74 Therefore, phytochemicals are secreted by plant roots via passive or active processes by employing a variety of transport mechanisms.72,75 Low-molecular-weight compounds are usually released by a passive mechanism. The process of direct passive diffusion depends on many factors, such as the polarity of compounds, membrane permeability, and cytosolic pH.72 Other compounds, such as proteins, polysaccharides and secondary metabolites, are secreted by an active mechanism that involves different membrane-bound proteins.34,75 For example, the ATP-binding cassette (ABC) transporters are associated with many transport processes in plants, including root secretion.76–81 The multidrug and toxic compound extrusion family (MATE) exports various substrates across membranes.75,82 Additionally, other transporters such as the major facilitator superfamily (MFS) and the aluminum-activated malate transporter family (ALMT) have also been described.75,83,84

Evidence suggests that plants establish a favorable environment by actively recruiting specific members of the rhizosphere microbial communities through root exudates (Fig. 1).52,58,74,85–88 In fact, the type and composition of root secretion can alter the microbial dynamic, not only favoring the growth of microorganisms that can benefit plant health but also preventing the growth of harmful microbes.88–92 The exact mechanisms used by plants to shape their microbiome are yet unknown, but differences in the metabolite blends excreted into the soil are likely an important factor.32,93–96 Additionally, hormones involved in plant immunity, especially salicylic acid (SA, 2, Chart 4), play roles in shaping the root microbiome.97 Similarly, inducing the jasmonic acid (JA, 3, Chart 4) defense pathway significantly alters the rhizosphere microbial community, leading to the enrichment of microbes involved in plant defense.45 The presumed ability of a plant to select specific microbes may result directly from the chemical dialogue between the plant and its colonizers.31 Plants secrete a wide variety of signals, some of which affect both beneficial and pathogenic organisms and others that are known to affect only mutualistic microorganisms.54,70,96,98–100 Furthermore, during communication with beneficial partners, plants may also unintentionally attract opportunists.101–103 Therefore, root secretions may play symbiotic or defensive roles when a plant ultimately engages in positive or negative relationships.55,92

At the same time that root exudates shape the rhizosphere microbiome, these microorganisms also influence plant root exudation.34,104–108 For example, alterations in plant amino acid exudation have been observed in the presence of the microbial compounds phenazine (4), 2,4-diacetylphloroglucinol (DAPG, 5), and zearalenone (6) (Chart 1).109 Considering that certain amino acids [e.g., glutamic acid (7) and proline (8)] and amino acid betaines (e.g., glycine betaine, 9) (Chart 9) are involved in osmoregulation in bacterial cells,96,110 the modulation of root exudation may confer advantages to plant-associated and soil microorganisms. In addition, those microbes may also influence the plant metabolome and modulate the hormones involved in plant immunity.13,111,112

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Chart 1 Structurally diverse compounds, including vitamins, that act as signaling molecules during intra- and interspecies communication.
2.1.3. Recruitment of symbionts through chemotaxis and electrotaxis. Chemotaxis is an important mechanism for recruiting motile soil bacteria to the roots of plants, and it is critical for the establishment of bacterial associations with the roots of plants.34,53,113 Chemotaxis signaling is prevalent in bacteria that occupy soils and sediments.114,115 Through root exudation, a compound gradient is formed in the soil, attracting diverse motile bacteria (Fig. 1).30,33,85,116 Furthermore, the compounds found in root surfaces are believed to stimulate a chemotaxic response.53

Bacterial chemotaxis is initiated by the detection of extracellular cues via specific receptors.117 The chemotaxis signal transduction system was first described in Escherichia coli, enabling an understanding of the mechanisms involved in the navigation of this bacterium within compound gradients.117,118 Eighteen classes of chemotaxis systems have been identified, and most of them comprise systems that control flagellar-based motility, with one class that includes chemotaxis systems that control type IV pili motility and another class including systems that control other cellular functions besides motility.119

Different plant-associated bacteria present different numbers of chemoreceptors and types of chemotaxic pathways.53 Ligand sensing typically occurs indirectly via the phosphotransferase system and/or periplasmic binding proteins, which then bind to the corresponding chemoreceptors.120–122 However, the ligand specificity of most chemoreceptors is unknown, making it difficult to identify the compounds within root exudates that specifically attract bacteria.53

In addition to chemotaxis, electrotaxis also drives oomycete pathogens during plant colonization.123,124 Plant roots generate external electrical currents due to the transport of protons and other ions at the root surface. The generated electrical field is able to attract motile zoospores to the roots.30,123 Even so, the importance of electrotaxis to the chemotaxis responses of soil-borne pathogenic fungi and bacteria is unclear.125

2.1.4. Phyllosphere also harbors microbial symbionts. Similar to the rhizosphere, the phyllosphere constitutes an environment for numerous microbial species that share a close relationship.126 Definitions of the term “phyllosphere” have changed over time.127 In this review, we adopted the “phyllosphere” term to refer to all aboveground plants that are considered habitats for microorganisms.47 Unlike in the rhizosphere, phyllosphere microorganisms are exposed to acute fluctuations in environmental factors, such as temperature, humidity, and UV light irradiation, and they have to cope with limited nutrients.47 Unlike the rhizosphere environment, very small amounts of exudates may be present in the leaves.128 Thus, microbes may acquire organic compounds from the leaf cuticle and plant cell walls.129 Plant volatile organic compound (VOC) emissions play significant roles in determining the characteristics of the microbial communities that can be established on plant surfaces through their antimicrobial effects and their role as carbon sources, thereby promoting the growth of mutualists and preventing the establishment of detrimental microorganisms.130,131 Therefore, microbes should present favorable genetic traits for adapting to the phyllosphere environment.126,132 For example, Methylobacterium spp. are methylotrophic microorganisms that are capable of using the VOC methanol as a carbon and energy source, and it is available as a by-product of plant cell wall metabolism.126,133 In addition, Sphingomonas spp. are able to exploit a large variety of substrates, so it is important for them to overcome the scarce nutrition of leaf surfaces.126 The production of the plant hormone indole-3-acetic acid (IAA, 10, Chart 4) has been considered another favorable microbial trait because 10 has been involved in bacterial adaptations to stress conditions and is also a signaling molecule in plant–microbe interactions.132,134 The characterization of the leaf microbiota is still incomplete, but phyllosphere microorganisms comprise both epiphytic and endophytic microorganisms, and they are distinct from rhizosphere microbial communities.135 Epiphytic microorganisms are found on the cuticle, an exogenous wax layer of aerial plant surfaces that represents a barrier against invasive microorganisms.136 Bacteria are the most prevalent microbes that are encountered in the phyllosphere, although the overall bacterial complexity is reduced.126,129 Importantly, epiphytic microorganisms were recently shown to possibly affect plant scent, which allows plants to communicate chemically with other organisms. Surface-colonizing microbes can alter plant fragrances by producing their own VOCs or by metabolizing those emitted by the plant.137,138 In addition, microorganisms may alter the plant physiology and modify the production and emission of these compounds.130,136 For more details regarding VOCs in plant–microbe interactions, see Farré-Armengol et al.130 and Junker and Tholl,131 as well as references therein.

In considering the microbial colonization of the phyllosphere, the air and its aerosols represent one route of transmission for the Sphingomonas and Pseudomonas genera, which usually make up the phyllosphere communities.126,139 However, another study has shown a high degree of dissimilarity between airborne bacteria and the phyllosphere bacteria.140 Neighboring plants and plant debris constitute another important immigration source, because these bacteria have already adapted to the phyllosphere environment. Studies on rice (Oryza sativa) have indicated a closer relatedness between the phyllosphere and water communities than between the phyllosphere and rhizosphere communities.135 Together, these findings indicate that the origin of the bacterial phyllosphere microbes is much more variable than that of the root community (Fig. 1).47 Furthermore, a plant's ability to actively recruit microbes to the phyllosphere, as demonstrated in the rhizosphere, is unclear.132

In comparison to the rhizosphere and leaves, little is known about the microbial community in other plant organs, such as flowers, fruits, and seeds.141 Similar to the phyllosphere microbiota, bacteria are the most abundant colonizers in these plant parts. However, plant organs still present far fewer bacteria than the rhizosphere.142

2.1.5. Inter- and intraspecies signaling and signal interference. Regarding the chemical signaling involved in plant–bacterial interactions, quorum sensing (QS) compounds play important roles in establishing root–microbe associations in plants. QS is a type of cell density-dependent stimulus and response system that regulates some bacterial behaviors, such as the metabolic rate, propagation, and virulence.24,25 To arrange synchronized activities, bacteria secrete small molecules that act as autoinducers (AIs).143 For example, N-acyl homoserine lactones (AHLs) are used as AIs by Gram-negative bacteria,143 although AHLs are not exclusive to Gram-negative bacteria.144 In general, these molecules consist of a hydrophilic lactone ring and a carbon chain with varying lengths from 4 to 18 carbons, which modify their hydrophilic/hydrophobic properties.143 The N-(3′-oxo-hexanoyl)-homoserine lactone (3′-O-C6-HSL, 11, Chart 2) is known as AI-1. Apart from these Gram-negative bacteria, cell-to-cell communication has also been recognized in Gram-positive bacteria, yeast and filamentous fungi (Fig. 2).144–155 For instance, Gram-positive bacteria produce oligopeptides as AIs (e.g., ComX pheromone, 12, from Bacillus subtilis),156,157 and Streptomyces spp. produce gamma-butyrolactones (e.g., A-factor, 13) and methylenomycin furans (e.g., MMF1, 14) as signaling and QS molecules (Chart 1).158,159 Tyrosol (15, Chart 9) and farnesol (16, Chart 1) have been reported as QS molecules in yeasts,145,147 whereas the molecules responsible for QS signaling in filamentous fungi have not been chemically characterized.150 Additionally, the AI furanosyl borate diester, known as AI-2 (17, Chart 1), shows widespread occurrence among bacteria and is considered a universal signal for interspecies communication.155,160
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Chart 2 Chemical structures of N-acyl homoserine lactones (AHLs) and the mimic compound rosmarinic acid.

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Fig. 2 Plant–microbe and microbe–microbe chemical interactions. The outcome of interactions between a plant and its microbial colonizers depends not only on plant–microbe signaling but also on chemical communication among microbes. Microorganisms secrete chemical signals to communicate within species through quorum sensing (QS) molecules (e.g., 11, 13, 14, 15, 16, 17) and between species, including antibiotics (e.g., 174, 175), to outcompete challenging microbes. Additionally, microbes may also interfere with the QS signaling of competitors through quorum quenching (QQ) mechanisms. The small molecules used for intraspecies communication, such as the N-acyl homoserine lactones (AHLs), may also be used for inter-kingdom crosstalk. In Arabidopsis thaliana, short acyl-chain AHLs (e.g., 20) promote root modifications, while long acyl-chain AHLs (e.g., 23) induce plant resistance. However, the presence of bacterial QS molecules elicits plants to produce molecules that interfere with QS signaling, by mimicking AHL (e.g., 30) or decreasing AHL interactions with receptors (e.g., 31). QQ mechanisms also include the enzymatic degradation of QS molecules. Plants may also stimulate microbial QS (e.g., 10, 88).

Stereochemistry plays a key role in the biological activities of QS molecules, as such it is important in every biological system. For example, the Gram-negative bacterium Rhizobium leguminosarum produces the (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone [(3′R)-OH-(7′Z)-en-C14-HSL, 18, Chart 2], also known as small bacteriocin,161 which is fundamental for preventing excessive growth that might trigger a plant defense response.162 The configuration of the side-chain stereogenic center is more important than that of the homoserine-lactone part.162 While the natural isomer exhibited the greatest activity, the 3′S-isomers showed 100–500 times weaker activity.162 In the case of the pathogen Xanthomonas campestris pv. campestris, the causal agent of black rot in Arabidopsis and Brassica plants,162 its pathogenicity is mediated by the QS diffusible signal factor (DSF, 19, Chart 6).163 The importance of the cis-double bond configuration at the α,β position for the biological activity of 19 was demonstrated through stereochemistry–activity relationship studies.162,164 The relevance of knowing the absolute configuration of natural products lies in the essential information it provides for further studies ranging from total synthesis to the molecular mode of action of bioactive compounds.165 In addition, because microbial signaling molecules are produced in low quantities, chemical synthesis has become an alternative that provides sufficient amounts of the sample to compare the physical and biological properties of the investigated molecule with those of the natural product, and it therefore disproves or re-assigns a proposed structure.162

Apart from regulating microbial activities, the QS molecules produced by bacteria also elicit a range of plant responses that may be beneficial to host plants. For example, plants may react more efficiently to biotic challenges when exposed to QS molecules.26,166 AHLs can modify plant physiology, as evidenced by the root growth effects caused by changes in the auxin/cytokinin ratio after treating plants with N-(butanoyl)-L-homoserine lactone (C4-HSL, 20) and N-(hexanoyl)-L-homoserine lactone (C6-HSL, 21) (Chart 2).143,167 Interestingly, the dual role of AHLs in Arabidopsis thaliana has been shown; AHLs with a short acyl chain (20 or 21) seem to increase growth rate and primary root elongation, while AHLs with long acyl chains, such as N-(dodecanoyl)-L-homoserine lactone (C12-HSL, 22) or N-(tetradecanoyl)-L-homoserine lactone (C14-HSL, 23) (Chart 2), induce resistance. This process is known as the AHL-induced resistance phenomenon, or AHL-priming (Fig. 2).143,166 In other plant species, the impact of AHLs may differ. For example, the N-(3′-oxo-tetradecanoyl)-L-homoserine lactone (3′-O-C14-HSL, 24, Chart 2) produced by Sinorhizobium meliloti enhanced nodulation in Medicago truncatula, while other AHLs had no effect.143,168 The N-(3′-oxo-decanoyl)-L-homoserine lactone (3′-O-C10-HSL, 25) was able to induce adventitious roots in mung bean plants, while unsubstituted N-(decanoyl)-L-homoserine lactone (C10-HSL, 26) or C12-HSL (22) was not able to induce the same effect (Chart 2).143,169 Plant responses to AHLs depend not only on AHL structures but also on their concentrations and plant species.170 Another interesting characteristic related to the effect of AHLs on plant physiology is the transport and location of these molecules. A negative correlation was observed between the length of the acyl chain and the transport rate of AHLs inside root and shoot tissues.171 For example, short-chain AHLs, such as C6-HSL (21), can be relocated into leaves after being applied to the roots, while long-chain AHLs, such as 3′-O-C14-HSL (24), were not transported in Arabidopsis.143,172 As previously mentioned, AHLs can induce plant resistance, and JA/SA-dependent pathways were postulated for AHL priming.166 In Arabidopsis, the crosstalk between SA (2) and oxylipins, such as JA (3) and its derivatives methyl jasmonate (MeJA, 27) and jasmonoyl-L-isoleucine (JA-Ile, 28) (Chart 4), is important for long chain AHL-priming and may involve the activation of the stomatal defense response.143,166 However, differences can be found in other plant systems. For instance, both short- and medium-length carbon chain AHLs from Serratia liquefaciens and Pseudomonas putida can induce systemic resistance in tomato plants against the fungal pathogen Alternaria alternata, and it seems to depend on SA (2)- and ethylene (ET, 29)-related defense reactions (Chart 4).143,173

In addition to plant physiological changes and induced resistance, QS bacterial molecules also elicit the production and secretion of compounds that mimic QS molecules of bacteria in plants (Fig. 2).174–177 AHL mimics, including mimicry molecules, target different steps of QS regulation178 and specifically stimulate or inhibit the AHL receptor of bacteria engaged in mutualistic or pathogenic relationships with their host plants.179,180 Similarly, it was observed that synthetic AHL analogs can also trigger different responses depending on the AHL receptors,181 while some receptors seem not to be susceptible to the action of signal mimics.170,174,182 A recent study has shown that plants secrete rosmarinic acid (30, Chart 2) upon infection by Pseudomonas aeruginosa. This mimic compound competes with C4-HSL (20), the natural ligand of the bacterial QS regulator RhlR, and it induces QS-mediated responses such as biofilm formation and the production of virulence factors. Therefore, it seems that rosmarinic acid secretion is a plant defense mechanism in which a premature QS response in P. aeruginosa is stimulated, interfering negatively with its pathogenicity.175 Additionally, D-(+)-catechin (31, Chart 8) interferes negatively with the perception of C4-HSL (20) by RhlR of P. aeruginosa, leading to a reduction in the production of QS signals and virulence factors.183

The process of interference in microbial QS signaling is known as quorum quenching (QQ).24,26,170,184,185 Plants may use different mechanisms to prevent bacterial QS signaling, including the inhibition of AI biosynthesis and/or secretion, the enzymatic degradation of these molecules, and even the disruption of their binding to receptors and regulators.154,170,186 Additionally, plants may also stimulate QS signaling in plant-associated bacteria.176 For example, plants produce IAA (10) and cytokinins that influence QS, the type III secretion system (T3SS or TTSS) and gall formation activity in Pantoea plantarum pv. gypsophilae.187 Flavonoids that are produced by legumes increase the expression of AHL synthetic genes in Rhizobia (Fig. 2).188

As expected, chemical signaling among different microbes also occurs and certainly has consequences for plant–microorganism interactions. Microbial populations can use distinct compounds to communicate within and between species. During interspecies communication, the AIs produced by one species can modify the behavior of its competitors. However, competing microbes can disrupt each other's QS signaling through the QQ process (Fig. 2).24,26,184,185 By interfering with QS, beneficial microorganisms protect plants by preventing synchronized pathogen signaling and plant colonization.184,185 For example, microbes may use enzymes such as lactonase and acylase to degrade AHLs184 or produce VOCs that interfere with bacterial AHL production.189

Therefore, QS molecules enable intra- and inter-microbial communications as well as signaling with host plants, thereby maintaining symbiotic associations and colonization within plants.185 Accordingly, AHLs and strigolactones (SLs), which will be discussed later, are important signaling factors in cell-to-cell communication other than cell density-dependent signaling, and they participate in the interplay between plants and microorganisms. Furthermore, other molecules are also involved in chemical signaling, such as the microbial VOCs 2,3-butanediol (32) and acetoin (33) (Chart 9), and diketopiperazines.19,27,34,59,100,190–193 For example, P. aeruginosa produces the diketopiperazines cyclo(L-Pro-L-Val) (34), cyclo(L-Pro-L-Phe) (35), and cyclo(L-Pro-L-Tyr) (36) (Chart 9) that modulate auxin signaling and promote A. thaliana growth.192 The role of microbial VOCs in plant–microbe interactions with respect to their effects on plant growth and health has been reported.194,195 To a lesser extent, the role of plant VOCs in plant–microbe interactions130,131 and that of the microbial VOCs in microbe–microbe interactions196 have been addressed, showing the need for more research in these fields. Additional examples of chemical signals are found in the following sections.

2.2. Modulation of plant immunity

2.2.1. Plant perception of microbial invasion through the recognition of molecular patterns. In considering the process of plant immunity, a first layer in the innate immune system of plants is based on the perception of pathogen-, damage- or microbe-associated molecular patterns (PAMPs, DAMPs or MAMPs) by transmembrane pattern recognition receptors (PRRs) (Fig. 3).197–202 Because not only pathogens but also other microbes were found to express molecular patterns that could activate a defense signaling cascade and plant immunity,31,200,203 the more generic term MAMP was proposed.201,204 While the terms MAMP and PAMP have been used interchangeably by many authors in plant immunology, the more generic term is preferred.205
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Fig. 3 The complex process of plant immunity modulation. Plants recognize beneficial and pathogenic microbes through microbe-associated molecular patterns (MAMPs or PAMPs), which include microbial secondary metabolites (e.g., 177). These microbial compounds interact with the transmembrane pattern recognition receptors (PRRs) and trigger pattern-triggered immunity (PTI or MTI), which leads to morphological and physiological alterations in plant cells, including callose deposition, stomatal closure, and the induction of ET (29) and secondary metabolites (e.g., 39, 40, 42, 45, 51). Microbes secrete effectors to evade PTI signaling (e.g., MiSSP7 protein and 38 from beneficial and pathogenic microorganisms, respectively) during a process called effector-triggered susceptibility (ETS). In turn, plants have evolved resistance genes (R genes), which encode the NB-LRR proteins responsible for recognizing specific effectors. Upon effector recognition, plants activate effector-triggered immunity (ETI), which leads to changes in the plant similar to what occurs during PTI, including cell death and defense signaling pathway activation [e.g., SA (2) and JA-Ile (28)]. Together, all these plant alterations lead to hypersensitive responses (HR) locally and to induced/acquired systemic resistance/tolerance (ISR, SAR or IST) systemically. This long-term immune memory enhances plant resistance to biotic and abiotic factors through the priming mechanism. Both beneficial and pathogenic microorganisms can modulate plant immunity by interfering with plant hormonal signaling. They may inhibit or induce specific pathways through the production of phytohormones (e.g., 10), phytohormone mimics (e.g., 37), or effectors.

Fragments of the building blocks of fungal and bacterial cell walls such as chitin, chitosan, peptidoglycans, glycoproteins, lipopolysaccharides (LPS), and many secreted components are examples of MAMPs in plants.31,206–210 A well-studied case is the recognition of bacterial flagellin as a MAMP through the FLS2 (Flagellin-Sensing 2 receptor).211 Additionally, secondary metabolites such as AHLs,173 siderophores,212 biosurfactants,213,214 and antibiotics215,216 can also be included as MAMPs.31,198 In addition, once many plant pathogens produce lytic enzymes to breach plant tissues, the resulting lytic products may also function as endogenous elicitors or DAMPs.198,217,218

2.2.2. Activation of plant-induced resistance and microbial evasion of the immune system. Upon colonization of the roots by specific beneficial microbes or infection by pathogens, plants can develop induced resistance.219 The response to PAMPs or MAMPs has been called PAMP-triggered immunity (PTI) or even MAMP-triggered immunity (MTI).197,205,220,221 Additionally, some authors have used the term “PTI” in a generalized manner, meaning pattern-triggered immunity.222 MAMP recognition also triggers the activation of mitogen-activated protein kinases (MAPKs) and calcium-dependent protein kinases (CDPKs), which are central signaling modules that transduce early PTI signals into multiple intracellular defense responses.28,223 The activation of PTI leads to callose deposition, stomatal closure, the production and accumulation of reactive oxygen species (ROS), and the induction of ET (29) and antimicrobial secondary metabolites (Fig. 3).222,224 These morpho- and physiological responses may be either dependent or independent of MAPK and CDPK activation.222,225

Pathogens have developed ways to avoid PTI signaling or prevent detection by the host through the production of effectors.219,220,226–228 The delivery of effectors by pathogens is known as effector-triggered susceptibility (ETS).205,229 In turn, plants have developed a second layer of defense named effector-triggered immunity (ETI), which is activated after detecting the pathogen effectors through intracellular NB-LRR proteins (proteins with nucleotide-binding and leucine-rich repeat domains).197,205,219,220,229 In fact, plants have evolved resistance genes (R genes) whose products mediate resistance to specific viruses, bacteria, fungi, oomycetes, nematodes or insects. R gene products are proteins, including NB-LRR, that allow for the recognition of specific pathogen effectors, either through direct binding or through the recognition of an alteration in a host protein in the presence of effectors (Fig. 3).229 Examples of microbial effectors include secondary metabolites, such as the toxins coronatine (37, Chart 4)230,231 and syringolin A (38, Chart 11)232 from Pseudomonas syringae. The specific virulence function of effectors has been difficult to uncover because a given class of microbes can be perceived through several PRRs, and pathogens have evolved different sets of effectors that can disrupt defense signaling.198,233

During ETI, the defense signaling pathways are activated, including the SA pathway. Together with ETI, a programmed cell death at the site of infection usually occurs, preventing biotrophic pathogens from entering living host tissue.219,234 This protection mechanism is known as the hypersensitive reaction or response (HR), and it is included in R gene-mediated resistance to pathogens.235 PTI and ETI also trigger induced resistance in distal, undamaged plant parts through long-distance signals that enhance the defensive capacity and confer resistance against future attack by a broad spectrum of pathogenic microbes, and against herbivorous insects.219,236–239 This long-term immune memory is known as systemic acquired resistance (SAR). SAR is acquired upon local induction by a pathogen and is SA-dependent.219,234,238–240 Similarly, the plant response to MAMPs of beneficial microorganisms is named induced systemic resistance (ISR).31,197 The terms SAR and ISR are considered synonymous, but some authors refer to SAR when the systemic resistance is triggered by a pathogen or is demonstrated to be SA-dependent and to ISR when the systemic resistance is triggered by a beneficial microbe or is demonstrated to be SA-independent.31,219 ISR and the involved signaling molecules are responsible for enhancing a plant's innate immunity, enabling plants to react more efficiently to biotic aggressors through a mechanism known as priming.26,31,241 Lastly, while ISRs are correlated with biotic stresses, some authors have proposed the term “induced systemic tolerance” (IST) for the plant responses that are induced by beneficial micro-organisms, such as plant growth-promoting rhizobacteria (PGPR), that result in enhanced tolerance to abiotic factors (Fig. 3).194,242

2.2.3. Plant secondary metabolites act as chemical defenses. During ISR, plants can defend themselves against pathogens through the production of secondary metabolites (Fig. 3). As mentioned earlier, during root exudation, plants constitutively secrete both low- and high-molecular-weight compounds.60,64,243,244 Secondary metabolites with antimicrobial activity that are constitutively produced by plants are called phytoanticipins.92,245 Inducible compounds with antimicrobial activity that are produced by plants during pathogen infections are known as phytoalexins.92,221,245 Usually, β-glucosidases hydrolyze the glycosylated phytoanticipins upon tissue disruption, which results in the release of the bioactive agent aglycone.246–248 For instance, the active compound 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA, 39) is derived from the glycosylated DIMBOA (DIMBOA-Glc, 40) phytoanticipin (Chart 3). The production of 39 was urged upon mycorrhization of maize,249 and this benzoxazinoid also acts as a chemotaxis molecule, recruiting the plant-beneficial rhizobacterium P. putida in a competitive soil environment.60 A similar pattern is also observed for other plant defenses, such as glucosinolates and others, that are also activated only in response to damage.248 The biosynthesis of phytoalexins is induced in many plant–microbe interactions upon HR. The biosynthesis of phytohormones that act in defense signaling is also induced upon HR to prompt disease resistance (Fig. 3).235
image file: c7cs00343a-c3.tif
Chart 3 Phytoanticipins and phytoalexins: the plant secondary defense metabolites that are exuded.

For example, the diterpene rhizathalene A (41, Chart 3) is a phytoanticipin that is produced by the non-infected plant A. thaliana and is released by its roots. This compound was found to be a local antifeedant in the belowground zone that is directly involved in defense against root-feeding insects.250 Some benzoxazinoids, which are produced by grasses, play roles in plant defense against herbivorous insects and pathogens, and they also present allelopathic activity against competing plants.251–253 For clarification, allelopathy is a term that is used to describe the phenomenon in which a plant or microorganism can influence the growth and development of another organism positively or negatively by releasing chemical compounds into the environment.254 A variety of glucosinolates, such as sinigrin (42), glucotropaeolin (43) and gluconasturtiin (44) (Chart 3), are also activated upon plant damage.248 These allyl (42), benzyl (43), and phenethyl-glucosinolates (44) are the origin of allyl (45), benzyl (46), and phenethyl-isothiocyanates, respectively (47) (Chart 3). The antimicrobial activities of glucosinolate-derived isothiocyanates have been demonstrated to be dependent on the side chain size and modifications.255

In addition, the production and release of constitutive defense compounds can be increased upon establishment of positive or negative microbial interactions. The diterpene momilactone A (48, Chart 3) is secreted into the rhizosphere by non-infected rice. However, infestation by the blast fungus Magnaporthe grisea leads to the accumulation of this antifungal compound in leaves,235,256,257 showing both phytoanticipin and phytoalexin properties. Experiments have shown that the fungus M. grisea is able to metabolize and detoxify 48in vitro, a possible strategy for overcoming the toxicity of this defense compound and succeeding in plant colonization.235 In addition, 48 also acts as an allelochemical, inhibiting the growth of the roots and hypocotyls of cress seedlings.257 Furthermore, the concentrations of the constitutive iridoid glycosides aucubin (49) and catalpol (50) (Chart 3) in the roots of Plantago lanceolata were increased in the presence of nematodes, while soil microbes led to enhanced aucubin (49).258

Several examples of phytoalexins have been reported, including camalexin (51, Chart 3), an indolic compound derived from tryptophan.259 The MAMP flagellin 22, a synthetic 22-amino acid polypeptide that corresponds to a highly conserved region of eubacterial flagellin, triggers the production and exudation of 51 by A. thaliana roots.260 Reports have also shown that phytopathogenic fungi metabolize 51 into less toxic products.261,262 The microbial ABC transporter may also extrude plant defense products, and it was proposed as a virulence factor that increases tolerance of the pathogen Botrytis cinerea to camalexin (51).263 The biosynthesis of this compound is regulated by different signaling defense pathways, in which the phytohormones SA (2), JA (3), ET (29) and auxins play major roles.264 In addition, MAPKs have been involved in the induction of 51 accumulation in Arabidopsis plants.265 Similarly, the biosyntheses of other phytoalexins are regulated by phytohormones, transcriptional regulators, defense-related genes, and phosphorylation.264–266 For example, EIN2-mediated ethylene signaling was shown267 to induce the production of capsidiol (52) (Chart 3), a sesquiterpene phytoalexin involved in post-invasion defense in Nicotiana benthamiana against Phytophthora infestans.268 The involvement of ET signaling in the pre-invasion defense of N. benthamiana against P. infestans was also demonstrated through diterpene secretion via NbABCG1/2,268 which were predicted as exporters of 52.269 Many VOCs produced by plants also act as inhibitors of microbes,270 and some of them may be considered as phytoalexins because of their induction upon pathogen attack. After fungal infection, terpenoids play a major role as induced defensive VOCs.271–273 For a comprehensive review on phytoalexins, see Ahuja et al.,264 Jeandet et al.,265 and Jeandet274 and references therein.

Plants also produce small peptides for defense. They can exhibit direct antifungal activity or act as chemical signals that modulate plant defense pathways.275,276 For example, in response to cell damage, tomato plants produce and release the small peptide systemin that mediates the activation of the JA signaling pathway,277 which increases resistance against necrotrophic pathogens. A recent study suggested that phytosulfokine (e.g., PSK-alpha, 53, Chart 3) signaling in plants regulates structural rearrangements in plant cells that ensure the successful feeding of biotrophic plant pathogens, such as the oomycete Hyaloperonospora arabidopsidis and the root-knot nematode Meloidogyne incognita.278 The PSKs are tyrosine-sulfated peptide hormones that are involved in cell differentiation.279,280 Rodiuc and collaborators demonstrated the involvement of PSK signaling in Arabidopsis in an infection by evolutionarily distant pathogens.278 The PSK signaling showed a positive influence on a downy mildew infection through PSK receptor 1 (PSKR1), stimulating the H. arabidopsidis infection cycle; it promoted disease susceptibility to Ralstonia solanacearum, enabling bacterial multiplication; and it played a role in the growth and maturation of feeding cells in a root-knot disease caused by M. incognita.278 Additionally, PSK signaling has been identified as a link between plant development and disease susceptibility.278

Interestingly, mycorrhizal symbionts can contribute to plant defense by promoting plant–plant communication, for instance through the transmission of signals related to a herbivore or pathogen attack.281–283 Signaling molecules can be transported through the so-called common mycorrhizal network (CMN), which is a network formed by mycorrhizal fungal hyphae that are associated with different plant individuals, and it connects them.284 Plant–plant communication through the CMN is a phenomenon that is still not well-described, and it is an interesting and important open field in plant signaling. For more information on this topic, please check Gilbert and Johnson.284 The CMN can reportedly transport allelopathic compounds, helping the plant host to spread these chemicals, since this network can reach longer distances than the root and limit the exposure of the compounds to the soil, decreasing compound loss by degradation, sorption, and complex formation, and increasing the plant bioactive zone.283,285,286

2.2.4. Phytohormone signaling pathways and the modulation of plant immunity. Considering the wide range of microbial interactions from mutualistic to antagonistic, plant immunity must be modulated.240 Induced resistance is regulated by a complex network of signaling pathways that are interconnected and share signaling components.31,219,240,287 Hormone crosstalk, which refers to the interactions of diverse hormone signal transduction pathways, provides the plant with the capacity to regulate its immune response to invaders in a cost-efficient manner.234,240,288 Plants usually maintain both constitutive and inducible defenses.288

The phytohormones SA (2) and JA (3) and their derivatives play a central role in immune system regulation, acting antagonistically.221,240,289,290 In addition, other hormones such as ET (29), abscisic acid (54), auxins [e.g., IAA (10) and its form conjugated to aspartic acid, namely IAA-Asp (55)], gibberellins (e.g., gibberellic acid, 56), cytokinins (e.g., zeatin, 57), brassinosteroids (e.g., brassinolide, 58) (Chart 4), SLs [e.g., (+)-strigol, 59, Chart 5] and nitric oxide (NO) also take part in plant immunity, fine-tuning the hormonal balance to improve resistance in different situations.205,219,291–300

image file: c7cs00343a-c4.tif
Chart 4 Plant hormones (except strigolactones), their derivatives, analogs, precursors and the JA-Ile mimic compound coronatine.

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Chart 5 Natural strigolactones (SLs), their synthetic stereoisomers and some analogs.

SA (2) and JA (3) regulate defense responses to different types of microbes, which can be classified according to their trophic relations with host plants. Necrotrophic microbes acquire nutritional goods through the production of phytotoxins and enzymes that degrade host cells, destroying plant cells and tissues. Biotrophic microbes obtain nutrients from living cells, commonly through specialized feeding structures. Hemi-biotrophic microorganisms present both nutritional states, depending on the stages of their life cycle.240,301,302 The SA (2) defense pathway acts against biotrophic and hemi-biotrophic microbes and is induced upon recognition of MAMPs or effectors from both pathogens and beneficial microbes.205,240,301,303–305 In effect, SA (2) acts not only in plant defense signaling but also as an antimicrobial compound.234,289,306 However, the JA (3) pathway is effective against herbivorous insects and necrotrophic pathogens.301 The biosynthesis of JA (3) via the oxylipin biosynthetic pathway is induced upon pathogen or insect attack. JA (3) can then be metabolized to MeJA (27) or conjugated to amino acids.307,308 JA-Ile (28) is the biologically and highly active form of the JA (3) hormone.308 The JA signaling pathway is divided into two different branches.240 One is used to recognize necrotrophic pathogens,309,310 whereas the other is involved in wound response and defense against insect herbivores311,312 and in the priming mechanism.313,314

The molecular basis of SA–JA crosstalk has been detailed elsewhere,240 and the interplay of different hormonal pathways has also been reviewed.240,299 During hormone crosstalk, specific defenses that induce resistance to one pathogen may cause the plant to be more susceptible to another.205,288,315 Nevertheless, the non-simultaneous recruitment of different defense pathways has been considered a cost-saving strategy during plant evolution.288,316 As mentioned before, the JA and SA pathways generally antagonize one another.221 In addition to their importance in defending against biotic factors, the SA and JA pathways and their interactions have also been implicated in adaptive responses to abiotic stresses.240,317–319 It is important to emphasize that SA and JA defense signaling can be modulated by other plant hormones. In this context, ET (29) has been considered a critical third player in mediating immune pathway crosstalk during defense responses, acting as an inducer or repressor of the signaling components and pathways involved in plant immunity.240,288,299 ET (29) is involved in a multitude of plant responses, and it plays a crucial role in plant stress. Stress responses are exacerbated and root growth is impaired under high levels of 29.320 Additionally, the role of the auxin IAA (10) in plant immunity has also been investigated. This phytohormone is primarily known to be involved in plant growth and development; however, high levels of 10 and enhanced IAA signaling have been implicated in plant susceptibility to pathogens through different mechanisms, such as inhibiting the HR (hypersensitive response), favoring pathogen colonization and pathogenicity.134,321 High concentrations of IAA (10) also suppressed the SA pathway in plants, increasing susceptibility to biotrophic microbes.299,321

2.2.5. Symbiotic microbes interfere with plant immunity. Interacting microorganisms can alter the plant immune system and phytohormone signaling through the production of phytohormones, phytohormone mimics, or effectors that target hormonal pathways (Fig. 3). Microbes can manipulate plant immunity to either promote disease or establish beneficial interactions.14,85,205,240,299,322 In fact, not only pathogens but also beneficial microbes have evolved effectors that are delivered inside the host plant cell to manipulate hormonal signaling.205,323 For example, the systemic resistance response that is induced in plants by beneficial rhizobacteria can be regulated through different signaling pathways,125 either by JA (3) and ET (29),14 or SA (2),324 or by activating both the SA and JA pathways.325 Similarly, pathogens can manipulate these pathways to their own benefits.26,205,299 Beneficial microbes can modulate ET (29) levels by enzymatically degrading the ET precursor 1-aminocyclopropane-1-carboxylic-acid (ACC, 60, Chart 4). The enzyme ACC deaminase can then cleave the plant-produced ACC into ammonia and 2-oxobutanoate. This cleavage causes both the alleviation of plant stress and phytostimulation, resulting in drought tolerance and increased plant growth.13,242,326–328 Therefore, lowering plant ET (29) levels benefits plants because it improves resistance to a variety of biotic and abiotic stresses.34 In addition, microorganisms can interfere with other phytohormone signaling. For example, some bacteria and fungi naturally produce IAA (10) and can modulate auxin signaling. As a result, plant root development and growth are altered, which may improve plant fitness, but pathogen colonization may also be favored, which increases plant susceptibility to pathogens.26,134,190,329 Thus, microbial IAA (10) has both beneficial and deleterious effects on host plants.

Lastly, the chemical signaling involved in plant immunity not only limits the growth of pathogens and enables communication with symbionts, but it also serves to structure the microbial communities in the phyllosphere and rhizosphere.330 Specific cases of plant immunity modulation by the hosted microbes will be discussed below.

2.3. The plant holobiont: a diverse and interacting community

As demonstrated in the previous sections, microorganisms and plants are actively interacting through diverse signaling mechanisms, mutually influencing each other's physiology and fitness. The combination of the plant host and its microbial symbionts can be called a holobiont, emphasizing how all these organisms function together. Therefore, they should not be studied as autonomous entities, but rather as a biologically and chemically complex community.331,332 As examples of the complexity of the plant holobiont, the symbionts mycorrhiza and rhizobia, which have been broadly studied from the perspective of their role in nutrient acquisition, were also shown to influence the interactions among plants and herbivores by interfering with defense-related VOC production.333,334 It has also been shown that the association with mycorrhiza assists in plant defense in a broader way by priming it, in a process called mycorrhiza-induced resistance. For the establishment of this symbiosis, one important step is to modulate the plant defense response. This step activates plant immune responses systemically, priming the plant against future attacks by pathogens and pests and leading to a more efficient defense response.335 For more details on the mycorrhizal influence on plant immune responses, please consult Jung et al.335 and references therein. Furthermore, the presence of mycorrhiza can influence bacterial attraction to the root by interfering with the root exudate composition, which is an important player in defining the rhizosphere community known as the mycorrhizosphere. The attracted microbiota includes PGPR, which can protect plants against pathogens by also priming the plant immune response through the action of MAMPs and QS molecules.102 The mycorrhiza is, therefore, an interesting example of diverse and complex interactions among many more that might occur in the plant holobiont, shedding light on the importance of exploring symbionts through different and more holistic approaches.

Several studies have shown that microbe–microbe interactions are widespread, and they influence many phenotypic and metabolic traits.336–339 Therefore, it is expected that the complex holobiont comprises not only host–microbe interactions but also microbe–microbe interactions, constituting a consortium inside the host. However, the majority of the knowledge gathered so far regarding the plant holobiont has been acquired by studying either axenic cultures or binary interactions between plants and microbes. Therefore, signaling in this context is described in a simplistic way, in which one partner sends a signal and the other receives and responds to it without third-party interference. Additionally, there is a huge knowledge gap regarding microbe–microbe interactions, which have attracted more attention in recent years. For example, even though endophytic communities are diverse, it is not known how this community behaves inside the plant, and bacteria and fungi are usually investigated separately.340 It is suggested that interactions among the endophytic community and the plant host may even influence the interactions between plants and other microbes,340 highlighting the importance of a holistic study of plant microbiota. An interesting study exemplified that complex interactions among symbionts might occur and be important to the plant host. Santhanam et al.341 demonstrated that a core consortium composed of five bacterial isolates can protect the plant host against fungal diseases, but the individual isolates did not exhibit this property.

Even for well-described cases of plant–microbe symbiosis, there are still gaps regarding complex interactions. For example, despite the fact that the rhizobia and mycorrhiza symbionts can co-exist in nature, both have been widely studied separately, even though they share similarities in their signaling pathways.342 An interesting study examined plant biomass and nodulation when co-inoculating strains of mycorrhiza and rhizobia, in the presence or absence of nitrogen and phosphorus addition.343 A synergistic effect between rhizobia and mycorrhiza symbionts on plant growth was observed, regardless of nutrient addition. Moreover, the presence of mycorrhiza can increase the nodule numbers, even under nitrogen fertilization.343 The interaction among plant–rhizobia–mycorrhiza was also investigated on a molecular basis through RNAseq transcriptomics.342 In addition to showing a synergistic effect between microbial symbionts on plant performance, this study also revealed that approximately 10% of the genes with altered expression were influenced by both symbionts, including some nonadditive effects on some genes related to nutrient metabolism, exemplifying cases of interactions between them. More interestingly, the presence of rhizobia interfered with the gene expression of mycorrhiza, highlighting the complex interactions that might be occurring inside the plant host which still remain to be explored.342

If we consider the rhizobia–plant symbiosis alone, there is still a huge knowledge gap about its complexity, even though this symbiosis has been studied extensively over the past few decades. The signaling pathway that leads to nodule formation has many steps that have already been described in the literature, and it will be addressed in the following topics. Nodules are special organs for nitrogen fixation, and it has been demonstrated that rhizobia are not the only inhabitants of these special structures; for more details about the biodiversity inside the root nodule, see Martinez-Hidalgo.344 However, most of the studies on the signaling involved in nodule development and function do not consider the huge diversity of microbes that co-exist with rhizobia inside this special organ. Some of the inhabitants of the nodule were shown to harbor genes related to nodulation in their genomes, and they can even elicit nodulation, leading to the speculation that they might be important during rhizobia–plant signaling.345–348 In fact, the function of the nodule microbiota is largely unknown. It is suggested that all the nodule microbiota function together as a consortium, benefiting plant health and survival.344 It also remains to be described what interactions, if any, occur among these microbes that are sharing the same enclosed habitat inside the plant host.344 Studying plants and their associated microbes as a consortium leads to a holistic understanding of the signaling pathways among several species living in the plant holobiont, which is an important but still poorly explored field. The next topics will explain the currently available knowledge about specific signaling between plant–microbial symbionts, and some examples of more complex interactions among symbionts will also be provided.

3. Specific signaling in different cases of plant–microbial symbiosis

All the important processes and chemical cues involved in attracting microbes, interactions among them and with their host plants and the modulation of plant immunity have been addressed in the previous section. In the following section, we are going to address how those processes occur, specifically with regard to different interactions between microbes and plants, by considering their particularities.

3.1. Mycorrhiza and rhizobia

Plants can establish very intimate mutualistic symbioses with fungi and nitrogen-fixing bacteria in their rhizosphere; as the symbiosis starts, new tissues and particular organs dedicated to the symbiosis are developed, which are fundamental for sharing goods between the partners.27 As expected, these specific symbioses require well-orchestrated events that are mediated by a chemical dialog between partners.

One of the most widespread symbioses is the plant–fungi system, i.e., mycorrhiza. Approximately 90% of the plants harbor these symbionts.349 This group can be classified into two classes, namely ectomycorrhiza and endomycorrhiza. The ectomycorrhiza (EM) is established by fungi known as ectomycorrhizal fungi (EMF), which do not enter plant cells; instead, they colonize the intercellular spaces between the epidermal and outer cortical cells, forming structures called the Hartig net, and the tip of lateral roots, forming structures called mantles.349,350 This mutualism is mostly seen in temperate forests, and it has been described in approximately 6000 tree species;350 it is formed mostly by basidiomycete fungi, but it also includes ascomycetes and zygomycetes. This symbiosis dates back to approximately 180 million years and is the result of convergent evolution through a transition from a saprophytic lifestyle.350 In fact, EMF still maintain this lifestyle as facultative saprotrophs in soil.351 In this symbiotic system, the host provides fungi with up to 20% of the carbohydrates produced by photosynthesis, and fungi provide the plant with up to 70% of its nitrogen and phosphorus needs.352

Endomycorrhiza is formed by fungi whose hyphae actually penetrate plant cells, forming the symbiotic structure known as the arbuscule inside inner cortical cells.349,353 This is an old interaction that dates back to the beginning of land colonization, or approximately 460 million years ago, and it is widespread in nature, being found in approximately 200[thin space (1/6-em)]000 plant species.350 Endomycorrhiza is further sub-classified as orchid, ericoid and arbuscular mycorrhiza (AM),354 with the last being the most frequently studied one. Orchid and ericoid mycorrhizae are more specific cases of symbiosis. The orchid mycorrhiza is specific to the roots of orchids355 and ericoids are specific to the roots of some plants of the Ericaceae family.356,357 AM is more promiscuous with regard to the host,358 but it is always made up of fungi from the Glomeromycota phylum.353,359 The signaling involved in AM symbiosis has been extensively studied and will be covered in this review.

Some plants can establish intimate symbiosis with nitrogen-fixing Gram-positive bacteria belonging to the genus Frankia and nitrogen-fixing Gram-negative bacteria that form a diverse group called rhizobia.360 This last group of bacteria is well studied, and it will be described in detail in this review. It comprises diverse genera such as Azorhizobium, Bradyrhizobium, Mesorhizobium, Rhizobium and Sinorhizobium.361 In these symbioses with both Gram-negative and Gram-positive bacteria, a unique organ called a nodule is formed in the root.362 Inside the nodule, bacteria enter the root cortical cells and differentiate into a bacteroid form that fixes atmospheric nitrogen, and the plant host in turn provides nutrients such as photosynthates for its partner.362,363

A phylogenetic analysis of plant receptors for recognizing plant–symbiont bacteria/fungi signaling molecules together with the fact that these molecules have similar chemical structures and activate a common signaling pathway indicates that these symbioses share a common origin.364–367 Moreover, several analyses have reported genetic similarities between these two cases of symbiosis in genes related to their development.354,367–373 Because AM symbiosis predates rhizobia symbiosis,374 it is suggested that the latter has recruited some signaling pathways related to AM symbiosis.366,374–378

To develop the specific symbiotic structures properly and establish a harmonic interaction, the process of root mycorrhization and nodulation involves constant communication between partners, through exchanges of signaling compounds (Fig. 4). This process involves the attraction of partners, contact and symbiotic structure development (organogenesis) and the control of plant immune responses. Signaling compounds that are known to be involved in these steps will be discussed below for AM, EM and rhizobia.

image file: c7cs00343a-f4.tif
Fig. 4 Representative overview of the complex signaling between partners during the symbiotic interactions that plants can establish with the specific microbes present in the soil. Arbuscular mycorrhiza (AM), ectomycorrhiza (EM) and rhizobia are well-studied examples of intimate symbiotic relationship with plants. In all cases, the compounds released by the plant host act as cues to attract the specific symbiont. Strigolactones (e.g., 61) are well known for attracting AM fungi (AMF); flavonoids (e.g., 87) are known for attracting both rhizobia and EM fungi (EMF); and several amino acids (e.g., 95), carbohydrates (e.g., 96) and hydroxycinnamic acids (e.g., 98) also reportedly attract rhizobia. In addition to attracting the microbial symbionts, these compounds can induce the first morphological changes towards the establishment of symbiotic structures and the production of compounds that are important to symbiont signaling, such as Myc factors (78 and 79) by AMF, Nod factors (107) by rhizobia, and auxins (e.g., 10) and hypaphorine (90) by EMF. Other compounds play roles at different phases of the symbiotic relationship, such as cutin monomers (e.g., 80) and lysophosphatidylcholines (82) for AMF, and methyl jasmonate (27) for rhizobia. Despite being mutualistic symbionts, these three groups of microbes trigger the plant innate immune system, and therefore the system has to be modulated to establish a positive symbiotic status. The secretion of effector proteins has been described as being one of the strategies to achieve this end.
3.1.1. Signaling and plant–mycorrhiza mutualism. From the attraction of arbuscular mycorrhiza fungi (AMF) to organogenesis. Glomeromycota are obligate biotrophic fungi.349 They rely on a host to develop properly; therefore, it is fundamental to their survival to find the root of the right plant with which to establish symbiosis. Soil is a complex environment in a three-dimensional structure; thus, it is expected that plants and fungi have developed a way to help them to find each other. Chemical compounds act as signals to promote the plant–fungus encounter (Fig. 4).

It has been demonstrated that SLs (strigolactones), a specific group of terpenoid lactones produced by plants, are important compounds in this scenario (Fig. 4).379 SLs originate from C40 carotenoid metabolism pathways and are basically made up of a tricyclic lactone skeleton coupled to a methyl-butenolide through an enol ether bond.380 SLs are considered plant hormones that lead to morphological changes related to improved inorganic phosphate (Pi) uptake and more efficient Pi utilization, which include the inhibition of shoot branching and the stimulation of AMF interaction.379 In fact, SL production is increased in the roots when Pi concentration is low in the soil.358,381–383 This signaling event is the beginning of the establishment of a communication network between the symbionts, which leads to further intimate physical interactions that allow for their exchange of goods.

SLs are involved in chemotaxis by inducing changes in fungal metabolism related to germination and hyphal branching towards the host,349,384 which in turn is related to increased mitochondrial density and activity.99 This process is dependent on the concentration of SLs in the soil,385 and since these compounds are relatively unstable due to the enol ether bond, their detection in soil by fungi is a reliable indication that there is a host root recruiting symbionts nearby.354,358 Once roots are colonized by AMF, SL biosynthesis and secretion decrease,386 suggesting that the signaling involved in the attraction of AMF symbionts is fine-tuned.

There are approximately eighteen natural SLs384 that can be divided into two groups according to the stereochemistry at the B/C junction; one group has a C-ring in the β-orientation as in (+)-(3aR,5S,8bS,2′R)-strigol (59) and another group has the C-ring in the α-orientation as in (−)-(3aR,4R,8bR,2′R)-orobanchol (61) (Chart 5).387,388 The structural assignment of natural SLs relies strongly on the quality of the analytical, spectroscopic and chiroptical data.389 A review of the stereochemistry of natural orobanchol (61), the most common natural SL together with its acetate, was made in 2011 by comparing spectroscopic data with authentic synthetic compounds and performing analyses by circular dichroism,390 and recent synthetic efforts reinforce the correct structural assignment of 61.388 The correct establishment of SL structures is important because stereochemistry has a great impact on biological properties. The establishment and correction of SL structures has been comprehensively described.388–390 We have adopted the nomenclature suggested by Scaffidi et al. for SLs to avoid misunderstandings.391 Akayama and co-workers380 have tested several natural and synthetic SLs and their analogs to establish structure–activity requirements for hyphal branching-inducing activities in Gigaspora margarita. The two naturally occurring stereoisomeric forms of SLs are capable of inducing hyphal branching, and the compounds orobanchol (61) and fabacyl acetate (62, Chart 5) are among the most active ones. The moiety containing the lactone C-ring that is connected via enol ether to the methyl-butenolide D-ring is essential for hyphal branching activity. Reductions in the double bond of the enol ether linkage result in less active or inactive compounds. The presence of A or AB rings is also important for optimal hyphal branching activity. It has been observed that the deletion of the A ring or its replacement by a benzene ring in the tricyclic system reduces this activity.380 This finding suggests that plants can finely control AMF hyphal branching by defining the types and quantities of each SL compound released in their exudates. The presence of substituents at AB-rings can modulate their activity. For example, a hydroxyl group at C-4, such as in 61, increases the hyphal branching activity, possibly due to the hydrogen bond donor in binding interactions with the receptor site. In spite of the extensive structure–activity relationship studies on natural and synthetic SLs, their receptor in AMF has not been characterized yet. More recently, SLs have also been recognized as emerging key players in plant stress management,392 and it has been suggested that they are involved in plant immune responses against specific pathogens.392,393 In addition, the biological activities of SLs were also demonstrated when interacting with the α/β-fold hydrolases KAI2 (karrikin insensitive2) and AtD14 (dwarf14) of A. thaliana.391 Two natural deoxy-SLs, 5-deoxystrigol (63) and 4-deoxyorobanchol (64), and their non-natural enantiomers ent-5-deoxystrigol (65) and ent-4-deoxyorobanchol (66), plus four stereoisomers belonging to the GR24 group (67, 68, 69, 70) and two nitrile-debranone enantiomers (71, 72) were tested with regard to multiple physiological traits in Arabidopsis (Chart 5).391 It was observed that R-butanolide binds preferentially to AtD14 while S-butanolide binds to KAI2.391 In general, AtD14 mediates traits known to be regulated by SLs containing 2′R-butanolide, such as shoot branching, but surprisingly, non-natural SLs presenting 2′S-butanolide rings are also active through KAI2. These results suggest the necessity of investigating whether 2′S-SLs are actually biosynthesized by plants as signal molecules at non-detectable levels.391

In addition to SLs, hydroxylated fatty acids were also reported to play a role in chemotaxis in Gigaspora species, and several fatty acid chain lengths have been tested as inducers of hyphal growth.394 Interestingly, longer chains were more active; 2-hydroxytetradecanoic acid (73) was the most active, followed by 2-hydroxydodecanoic acid (74), while 2-hydroxydecanoic acid (75) and 2-hydroxyhexadecanoic acid (76) were not active (Chart 6). The different positions of the hydroxyl group also interfered with this activity; 3-hydroxytetradecanoic acid (77, Chart 6) was not active.394

image file: c7cs00343a-c6.tif
Chart 6 Fatty acids and their derivatives, and the long-chain alkyl alcohol 1,16-hexadecanediol.

During the germination process induced by SLs, AMF produce several compounds called Myc factors, which are fungal signaling molecules (Fig. 4).28 These compounds induce lateral root development by increasing the area for mycorrhization and starch accumulation in the roots395 by stimulating the common symbiosis signaling pathway known as CSSP or Sym.349,353,396 In mutants with impaired Sym pathways, AMF are unable to establish symbiosis.353 When Sym is triggered, an intracellular Ca2+ spiking occurs, and it is suggested that this spiking activates the calcium- and calmodulin-dependent serine/threonine protein kinase (CCaMK), which in turn activates the transcription of essential genes for symbiosis establishment. Luginbuehl and Oldroyd reviewed the CCaMK downstream signaling pathway and resulting cell changes.397

Several investigations have been pursued to uncover the chemical nature of the Myc factors. Two classes of chitin oligomers (oligosaccharides) can be cited as potential candidates: chitooligosaccharides (COs, 78) and lipochitooligosaccharides (LCOs, 79) (Chart 7), both showing variable structures and activities.384,398,399 COs (78) are present in germinating spore exudates, and short-chain COs (CO4/5) are produced in higher quantities when spore germination is induced by SLs.400 Pathogenic fungi also release CO4/5 in their exudates, but in this case, Ca2+ spiking is not observed. The difference is that pathogenic fungi also release long-chain COs (CO8), and this compound is known to trigger plant immune responses; consequently, it was hypothesized that the presence of CO8 inhibits the CO4/5 Ca2+ spiking response.400 Interestingly, studies have shown that when the host plant M. truncatula is under the AMF symbiotic establishment process, it produces some chitinases that could break down long-chain COs into CO4/5, preventing a possible immune response against AMF and increasing the symbiotic response.400,401 However, it is worth mentioning that for tomatoes and rice, CO8 also activates symbiotic responses when added at lower concentrations.402 Therefore, more comprehensive studies are necessary to understand the structure–activity/concentration relations for COs (78).

image file: c7cs00343a-c7.tif
Chart 7 General structures of Myc and Nod factors.

Diverse LCO (79) structures have been isolated, namely sulfated (sMyc-LCOs) and non-sulfated LCOs (nsMyc-LCOs) with four or five N-acetylglucosamines that can be acylated at the non-reducing end of the chitin oligomer.384 As expected, different structures exhibit different activities. Regarding the presence of sulfur on their structures, nsMyc-LCOs showed better activity with respect to AMF root colonization, whereas sMyc-LCOs were more active at lateral root formation; yet, the mixture of s/nsMyc-LCOs gave the best stimulus in both cases.399 LCOs are produced in minute concentrations, which makes it difficult to study their activity and it is most likely that many other LCOs have not been identified yet.384

The signaling between AMF and their plant host during the development of the actual symbiotic structures has been investigated and described. Once AMF reach the host root, the next fundamental step is the formation of a pre-symbiotic structure called the hyphopodium that is formed by mature hyphae.354 This is the first morphological change, and it is the beginning of intimate physical contact. The hyphopodium consists of a flattened structure that touches the root cells of the epidermis and facilitates the penetration of AMF into the root.403 Its formation seems to rely on host-specific chemical cues, because Gigaspora gigantea was capable of forming this structure in the presence of cell wall fragments originating from host roots, but not the cell wall fragments of a non-host root plant.404 Studies using M. truncatula mutants revealed that the RAM2 gene (RAM: Required for Arbuscular Mycorrhization) is related to hyphopodium formation. RAM2 encodes the glycerol-3-phosphate acyl-transferase enzyme that is involved in cutin and suberin biosynthesis, which are compounds that are present at the plant cell surface.405 In fact, the ram2 mutant fails at hyphopodium formation, and supplementation with cutin monomers, such as 16-hydroxyhexadecanoic acid (80) and 1,16-hexadecanediol (81) (Chart 6), restores this feature in ram2 mutants. These results indicate that cutin monomers act as plant signals for AMF hyphal differentiation into hyphopodium,405,406 an important step in the formation of the symbiotic organs.

At the same time, the host prepares the root environment to receive AMF alongside the hyphopodium. The underlying root cells start cytoplasm reorganization, forming a structure called the PPA (Pre-Penetration Apparatus). This structure directs the path for AMF colonization from the hyphopodium to the intracellular space, which is covered by the newly produced peri-arbuscular membrane (PAM), forming the actual symbiosis structure, or the arbuscule.353,407,408 This process of entering into the root cortex is under the control of the Sym pathway. During the development of the arbuscule, it is of high importance to ensure that phosphate-transporter genes will be expressed to guarantee Pi uptake and therefore keep the symbiotic structure.409 Thus, it is expected that there might be some signaling event controlling it. In fact, a compound was described as having an important signaling role in this step of symbiosis, and it is called lysophosphatidylcholine (82, Chart 6).410 This molecule is actually a product of phospholipid metabolism and was hypothesized to be a monitor of how much phosphate is available to the plant.410 From the attraction of ectomycorrhizal fungi (EMF) to organogenesis. The symbiotic structures of EMF are different in both anatomy and signaling when compared to AMF. In contrast to AMF, no role for SLs in EMF has been detected so far; no signaling was observed in the presence of this class of compounds.411 EMF chemotaxis towards their host is still unclear.

There are some compounds in root exudates that can lead to the germination of Suillus spores, specifically the diterpene abietic acid (83, Chart 1)412 and the flavonoids rutin (1), hesperidin (84), quercitrin (85), morin (86), naringenin (87), genistein (88) and chrysin (89) (Chart 8).413 Compound 1 was also described as a hyphal growth inducer in Pisolithus.69 However, studies on more EMF species are required to understand the complexity of plant signals that promote fungal chemotaxis towards the hosts.

image file: c7cs00343a-c8.tif
Chart 8 Plant flavonoids, including flavone, flavonol, flavanone, catechin, anthocyanidin, isoflavone, coumestan and some glycosylated derivatives.

To date, there is no evidence that there is any compound that would act as a Myc factor-like entity for activating Sym in the EMF host, and thus this signaling process remains to be described. Studies are needed to determine if LCOs (79) and/or COs (78) play a role in this symbiosis. Nevertheless, plant hormones play important roles in this system. Several studies have shown that EMF produce plant hormones such as auxins, cytokinins, gibberellins, abscisic acid (54), JA (3) and ET (29) (Chart 4).414,415 Plant hormones are involved in root development;300,416,417 therefore, EMF hormone production should influence root morphology before the establishment of the symbiotic structure.414

At the beginning of the interaction, there is an accumulation of auxin in the apex of lateral roots that does not require physical contact between the symbionts, revealing that EMF signaling molecules are involved in this process.418 This process interferes with root development, leading to more lateral short root growth and less root elongation in the vicinity of EMF hyphae, which is the normal root phenotype observed for plant–EMF symbiosis and has been shown to be induced by EMF.418–423 The phenomenon of auxin accumulation could also be explained in a scenario in which EMF would be delivering self-producing auxins. In fact, an increase in the mycorrhization process was observed in the presence of a mutant strain of Hebeloma crustuliniforme that overproduces the auxin IAA (10);424 furthermore, several microorganisms were described as auxin producers.424–426 Interestingly, 10 also influences EMF morphogenesis such as hyphal branching and consequently increases Hartig net formation.427 Auxin is undoubtedly an important signaling compound in this symbiosis; however, its complex signaling pathways that involve its production and morphological changes in both partners remain to be fully described. Another root morphological change during EMF colonization is reduced root hair elongation, which also involves fungal signaling.428 In response to root exudates, some EMF have increased production of hypaphorine (90, Chart 9) (Fig. 4), an amino acid derivative that induces this morphological change.421,428–431

image file: c7cs00343a-c9.tif
Chart 9 Simple small molecules acting in chemical signaling, such as amino acids and their derivatives, polyamines, organic acids, volatile organic compounds (VOCs) and simple sugars.

In contrast to AM, there is a gap in the literature regarding the signaling that occurs during the development of the EM symbiotic structures. However, the RAM2 gene was found in some EMF species432 and it was shown that after Laccaria amethystina hyphal attachment to Picea abies, a cuticle-like suberin layer was locally digested and released from the cell wall, and afterwards, hyphal branching was observed.433 Therefore, it could be suggested that suberin/cutin monomers also have a role in morphological changes leading to symbiotic structure formation during EM symbiosis.434 AMF and EMF modulation of the plant immune system. Despite the fact that these interactions are specific and intimate, fungi still have components that act as MAMPs, such as chitin, that are able to trigger the plant innate immune system, which blocks mycorrhizal colonization. The colonization process damages root cell walls, and thus mycorrhiza are also detected as invaders by the plant.14 In this sense, the host initially treats the mutualistic fungus as a potential intruder, which should in turn counteract this signal to gain symbiont status.14,435 Therefore, to succeed in plant colonization, fungi need to have strategies that circumvent the plant immune system.

Kloppholz and collaborators were able to detect an effector protein named SP7 in Glomus intraradices (AMF).305 This protein interacts with the transcription factor ERF19 (Ethylene-Responsive Factor 19), which is involved in the regulation of the ET signaling pathway.305 The overexpression of ERF19 in M. truncatula impaired mycorrhization, whereas its inactivation improved this process.305 Therefore, the secretion of effector proteins is one of the strategies for interrupting the immune signaling pathway and it allows for the establishment of this symbiosis (Fig. 4). The effector proteins MiSSP7s were also detected in the symbiont EMF Laccaria bicolor, and they have been demonstrated to be triggered by the flavonoids rutin (1) and quercetin (91) (Chart 8), which are present in Populus exudates.98,304 Studies on the L. bicolorPopulus trichocarpa interaction have revealed that MiSSP7 is produced only during symbiotic interaction and was detected in the hyphal mantle and Hartig net, but not in the free-living mycelium.436 A transcriptomic analysis of poplar roots indicated that MiSSP7 upregulates several auxin response-related genes.304 Moreover, as SP7, MiSSP7 action is involved in the plant hormonal immune system; MiSSP7 was shown to interact with JA signaling repressors in Populus, therefore blocking the action of this signaling pathway.437 Genomic analyses have shown a variety of effector-like proteins that are present in the genome of EMF,351,435,436 but studies including more EMF species remain to be performed to understand the role of effector proteins in EMF–plant associations.

Genomic analyses of some AMF and EMF have also shown that these symbiotic fungi harbor fewer enzymes that are involved in plant cell wall degradation compared to non-symbiotic fungi, such as carbohydrate-cleaving ones.350,436,438 Therefore, besides developing a strategy to combat the plant immune response directly, the fungus probably also experienced changes in its genome to reduce MAMP production. Gene losses are a common feature in the co-evolution of symbionts, and it is worth mentioning that these specific gene losses in AMF and EMF also imply that symbiotic fungi rely on the host supply of simple carbon sources.350

3.1.2. Signaling in plant–rhizobial mutualism. From rhizobial attraction to organogenesis. Regarding microbial symbiont attraction, the rhizobia seem to be more similar to EM, which involve flavonoids, but more studies are still needed for a better understanding of rhizobial bacteria attraction. The role of SLs in nodulation, as well as the role of flavonoids in mycorrhization, is still unclear and requires further research.57,368,439–441

Flavonoids are the most important compounds for establishing a symbiotic interaction with rhizobia, acting as cues for bacterial symbionts and for host specificity.442 Flavonoids related to rhizobial interactions are structurally diverse, including either glycones or aglycones, flavones, isoflavones, chalcones and coumestans.443,444 This class of compounds was reported to have many different roles in rhizobial interactions, most of them related to root modifications. Some flavonoids act as chemoattractors for rhizobia,57 such as luteolin (92), apigenin (93) and naringenin (87) (Chart 8).445–447 In addition to flavonoids, it is reported in the literature that several amino acids, such as L-asparagine (94) and L-lysine (95); carbohydrates, such as D-ribose (96) and D-glucose (97); and hydroxycinnamic acids, such as caffeic acid (98) and ferulic acid (99), also act as chemoattractants of rhizobia (Chart 9) (Fig. 4).448–450

Several flavonoids have been found to induce genes involved in nodulation (nod genes), triggering the production and secretion of compounds named nodulation factors (Nod factors) in the bacterial partner to mark the beginning of symbiosis development.101,440,451–455 Interestingly, not all flavonoids act as nod gene activators, and some can even repress their expression, such as coumestrol (100) and medicarpin (101) (Chart 8) in S. meliloti–alfalfa interactions.456 The isoflavonoids daidzein (102) and genistein (88) (Chart 8) act as inducers for Bradyrhizobium japonicum and Rhizobium sp. NGR234 (also named Sinorhizobium fredii NGR234 elsewhere) but as repressors for R. leguminosarum bv. trifolii and R. leguminosarum bv. viciae,443 exemplifying the role of flavonoids in host specificity. In addition to flavonoids, other compounds have also been reported as interfering in the expression of nod genes in rhizobia, such as the oxylipins JA (3) and MeJA (27) (Chart 4),457,458 the betaines stachydrine (103) and trigonelline (104),459 and the aldonic acids erythronic acid (105) and tetronic acid (106) (Chart 9).460

Nod factors (107, Chart 7) are structurally and functionally similar to Myc factors; they are a diverse class of lipochitooligosaccharides (LCOs) that possess a common backbone of four to five N-acetylglucosamines that are β1,4 linked, and the terminal non-reducing sugar is N-acylated with a 16–18 carbon fatty acid. Either end can experience modifications such as sulfation and glycosylation.28,362,461–464 Both the chemical structure and the concentration of Nod factors were demonstrated to be important for host specificity and nodulation.362,461,463,465–467 For instance, a study that used different mutant strains of Rhizobium meliloti showed that sulfation of Nod factors determines host specificity.468

Similar to Myc factors, it was also demonstrated that Nod factor perception by the plant leads to Sym activation and consequently triggers the CCaMK signaling cascade through intracellular Ca2+ spiking.28,469–471 For more details about Nod factor receptors and intracellular signaling, see Janczareck et al.442 Transcriptomic data and Nod factor feeding experiments in M. truncatula roots demonstrated that this signaling cascade leads to cytokinin accumulation, including compounds such as isopentenyl adenine (108), zeatin (57) and dihydrozeatin (109) (Chart 4), which are important for starting cell division and nodulation.442,469,472 Interestingly, cytokinin accumulation then induces ET (29) biosynthesis, and 29 in turn inhibits cytokinin accumulation by a negative feedback signal, suggesting a mechanism for regulating nodulation in the host.469

When the plant host senses Nod factors, the first morphological differentiation occurs in root epidermal cells and triggers cell division in cortical cells and meristem formation, which mark the beginning of nodule organogenesis.362 Interestingly, the nodulation process is inhibited in young root tissues through a regulation event called the autoregulation of nodulation (AON), which occurs during the early stages of nodulation to maintain a good balance between shoot and root development.362,473–475

It was reported that genes related to Nod factor production remain active in the nitrogen fixation zone of M. truncatula nodules, not only before infection, suggesting roles other than nodule organogenesis for Nod factors.476 It was also reported that Nod factors can partially suppress MTI,477 suggesting a role in mitigating plant immune defense during symbiosis, which would explain their production in the nitrogen fixation zone. Moreover, despite the very consistent and massive amount of data available in the literature showing the importance of Nod factors in initiating nodule organogenesis, it has also been reported that some rhizobia are able to engage in nodulation even when lacking nodulation genes.478–480 In this scenario, the T3SS (type III secretion system) is required in some cases to trigger nodule organogenesis.478–480 Therefore, despite being extensively studied, Nod factors still require more accurate and controlled experiments to reveal their real role in rhizobia–plant symbiosis.

During nodule development, flavonoids were also reported as controllers of auxin transport and breakdown, which is important because auxin accumulation in the root is required for proper nodule development.453,481–484 Therefore, flavonoids play multiple important and complex roles in the establishment of rhizobia–plant symbiosis.101,440 It is worth mentioning that for this system, in contrast to EM, the auxins produced by the microbial partner do not seem to interfere with symbiosis.485

After symbiont contact, rhizobial cells adhere to epidermal root hairs. As a result of the activation of Sym signaling, the root hairs start to deform and curl, entrapping the bacterial symbiont in a cavity called the infection pocket.486 Inside this cavity, bacteria continue to grow and promote plant cell wall degradation, forming a structure called the infection thread. This thread is made through the invagination of the plant plasma membrane that forms a path for bacteria to penetrate the cell.486 This infection thread might have an evolutionary origin in the pre-penetration apparatus of AMF.354 Exopolysaccharides (EPS) have been reported as important cues during the nodule organogenesis process.442,487 For example, studies using a mutant S. meliloti strain demonstrated that succinoglycans are required for the elongation of the infection thread through nodule cells. EPSs are polysaccharides that are secreted on the bacterial surface, and they also possess non-carbohydrate residues in their structure such as acetyl, pyruvyl, succinyl and methyl groups.442 Two primary groups can be highlighted: acidic EPS and cyclic beta-glucans. For a detailed review on EPS structures, biosynthesis and their roles in rhizobial infection, check Fraysse et al.,488 Janczarek et al.442 and Gosh and Maiti.489 Rhizobial modulation of the plant immune system. Similar to AMF and EMF, the rhizobia also stimulate plant immune responses and need to overcome them to succeed in root colonization.461 A transcriptomic study reported a high induction of genes related to plant defense 12 hours after B. japonicum inoculation, and interestingly, their expression decreased to the baseline within 24 hours, indicating an active suppression of the defense response.490

T3SS, a system that acts by injecting effector proteins into eukaryotic cells, was found in many rhizobia species (Fig. 4).491 The proteins secreted through the rhizobial T3SS system are called nodulation outer proteins (Nops)491 and can be induced by plant flavonoids.15 For example, NopM was described in Sinorhizobium fredii NGR234 as promoting nodulation on Lablab purpureus roots, and in N. benthamiana as an inhibitor of the plant defense response involved in inducing ROS.492

EPS have also been reported as suppressors of plant defense, such as succinoglucans (acidic EPS, also called EPS I).493 A study with B. japonicum mutants possessing altered EPS production showed that alterations in EPS composition led to the accumulation of phytoalexins,494,495 suggesting that this mutation affected the ability of the symbiont to control the plant defense responses.

3.2. Epiphytes and endophytes: microorganisms involved in diversified ecological relationships

The term “epiphyte” refers to any organism living on plants, including microorganisms.496 Epiphytes may engage in mutualistic, commensalistic and pathogenic relationships with their hosts.127,136 Analogously, endophytic microorganisms are microbial species that live inside plants. However, the term “endophyte” has evolved and refers not only to the location of these microbes but also to the nature of their association with the host.497 Thus, endophytes have been considered microorganisms that inhabit plant tissues for at least a part of their life cycle without causing any visible damage in their host plant,498 and they include bacteria, fungi, archaea, algae and amoebae.340

Culture-independent approaches have been used to determine the diversity of microbes that encounter plants;499–506 however, the difficulty of assessing the pathogenicity of these microbial members have raised questions about an appropriate definition of endophytes.340 In this new scenario, Hardoim and collaborators claim that the term “endophyte” should refer to the location only. A more general definition including all microorganisms which for all or part of their lifetime colonize internal plant tissues has been proposed.340 In fact, new approaches to studying endophytes may require researchers to consider some pragmatic revisions.

Some authors classify endophytes as obligate, facultative or passive, according to their lifestyle and colonization strategies.37,507 However, overlaps between these three groups should be considered. Passive endophytes are opportunistic microbes that do not actively colonize plants, randomly entering plant tissues under favorable conditions, such as open wounds. They primarily thrive outside plant tissues as epiphytes or soil microbes that sporadically enter the plant endosphere. Therefore, this group comprises the least competitive endophytic microbes.340,507 Facultative endophytes are free-living microbes that are present in the rhizosphere that eventually colonize plants. This group includes the PGPM (plant growth promotion microorganisms),37 including rhizobacteria (PGPR), other bacteria (PGPB) and fungi (PGPF). Lastly, obligate endophytes are unable to proliferate outside of plants and are commonly vertically transmitted via seed.37,507 In this regard, obligate endophytes are known as seed-transmitted microorganisms that should not be confused with seed-borne microbes, once the two terms are not interchangeable.508 Any microorganism that is found in seeds is considered a seed-borne microbe, and it is usually associated with the seed coat and not disseminated through the seed. However, seed-transmitted microorganisms are generally found within the embryo tissues and are transmitted from one generation to another through the seed.508 Members of the fungal genera Balansia, Epichloë, and Neotyphodium from the family Clavicipitaceae (Ascomycota)509 are examples of obligate endophytes.340 However, these microorganisms can also be horizontally transmitted via asexual or sexual spores.510,511 A large body of literature about endophytes is related to Epichloë species.512 For clarification, epichloae fungi consist of both Epichloë and Neotyphodium species, in which the genus Neotyphodium represents the Epichloë anamorphs and includes most asexual Epichloë descendants.513,514

Different authors consider the ecological relationship between plants and endophytes differently. Schulz and collaborators have hypothesized that there are no neutral interactions, but rather a balanced antagonism in which plant defenses outcompete fungal virulence to limit the development of disease.515 Alternatively, Hardoim and collaborators have suggested that the ecological relationship of most studied endophytes with their host plants is commensalism.340 Independent of the forces driving these interactions, the result of most studied plant–endophyte relationships may be a neutral non-mutualistic symbiosis that causes no damage to the associated partners. However, it is also important to consider that most studies on endophytes are not performed under field conditions, but in short-term laboratory and greenhouse trials.340,516 In addition, there are also endophytes that sustain mutualistic interactions.340 Approximately three decades ago, a defensive mutualism was the first hypothesis proposed to describe the endophyte–plant relationship in grasses,517 and it has still been endorsed.516,518 Nevertheless, defensive mutualism is most commonly detected in systemic and vertically transmitted grass endophytes compared to horizontally transmitted tree endophytes.516 Therefore, among all the reported endophytes, obligate and seed-transmitted endophytes are the more consistent examples of mutualistic endophytes.509,519 The endophytic PGPMs have also been considered mutualistic microbes.37,520 In addition, both mycorrhizal fungi and legume-nodulating rhizobial strains can be found inside roots, in the endosphere, forming endophytic associations with plants.340,354,509,521 This finding shows that discrimination among microbial group interactions with plants may be challenging.

Furthermore, endophytes may become phytopathogens under certain conditions, exerting negative effects on plants.125 Additionally, endophytic fungi may assume an epiphytic phase and exist as a latent pathogen that lives asymptomatically in the host plant for some time during their life.515,522–524 The balance between mutualism and antagonism depends on multiple parameters, including host and microbial factors and environmental conditions.515 Harmless microorganisms likely retain a virulence potential that may be revealed under certain variations in their habitat conditions.

Genomic analyses have identified important genes for plant penetration and colonization, and they have revealed differences among endophytes, nodule-forming symbionts, phytopathogens, rhizobacteria, and soil bacteria.340,525–530 Some properties are largely discriminative for endophytes compared to the other groups such as nitrogen fixation, protection against reactive oxygen and nitrogen species and responsiveness to environmental signals.340,525–530

Some fruitful traits are exclusively found in beneficial microbes, while harmful ones seem to be absent in these microorganisms. For example, Stenotrophomonas rhizophila was found to possess unique genes for the synthesis and transport of spermidine (110, Chart 9), a plant-protective compound, and for high salinity tolerance. In addition, heat shock proteins were absent in the plant-associated Stenotrophomonas strain, impairing their growth in humans.531 However, endophytic and pathogenic microbes may share similar functional features that are responsible for mechanisms involved in both beneficial and detrimental interactions. For example, T3SS (type III secretion systems) have been found in both pathogenic and beneficial bacteria.532 Similarly, the efflux pump SmeDEF is present in the human opportunistic pathogen Stenotrophomonas maltophilia, and it is involved in both antibiotic resistance533 and the endophytic colonization of plant roots.534 SmeDEF expression is triggered under the plant exudation of flavonoids, evidencing the role of this chemical signaling in the colonization of plants.534,535 Therefore, distinguishing nonpathogenic endophytes from pathogens is not trivial.340 The transcriptome dynamics of endophytes and their host plants may provide insight into plant–endophyte interactions.37,536,537 For instance, the PGPB Burkholderia phytofirmans senses when the plant is challenged by stress factors and adjusts its gene expression pattern to cope with the altered conditions.536 Therefore, the modern omics tools promise to take studies on endophytes to a higher level. Many aspects of endophytes and epiphytes that are not the focus of this review are thoroughly reviewed elsewhere.127,136,340,514

3.2.1. Plant attraction by endophytic/epiphytic microorganisms. The plant colonization process involves multiple chemical signals between plants and endophytes and among these microorganisms.37,340 It is known that plants select specific microbes in the soil or rhizosphere;50,128 however, it is not well understood how this selection specifically occurs. Plant–microbe communication begins with chemical signaling through root exudates, and these compounds have been reported to recruit many soil-borne microorganisms for the benefit of the plant.538–541 Chemical signals and nutrients in root exudates also enable microorganisms to identify appropriate hosts.16,58,539 Microbial performance is important during root colonization, including the expression of the appropriate genetic machinery, the chemotaxis response toward exudates, outcompeting microbial competitors, resistance against plant immunity, and the establishment of a niche within the plant tissue.30,37,128,539,542

The expression of relevant genes for the endophytic colonization of roots may be induced by root exudates.542 Most bacterial endophytes enter the plants via roots, but endophytes can also enter the plant via stomata, wounds, and hydathodes, or through flowers and fruits to a lesser extent.128,340 Compounds are also exuded in stems and leaves and may attract microorganisms.128 Both exudates and the plant immune system would finally select for the microbes that have evolved mechanisms to colonize the plant surface and endosphere.26 First, chemical attraction leads microbes to colonize the rhizoplane and other surfaces and subsequently penetrate the plant.340 Endophytes can move to other parts of the plant through vascular tissues, depending on the availability of plant resources.543,544 Some reports suggest that leaf microbial endophytes more likely result from the migration of root endophytic microorganisms within the plant than from colonization by microbes that were initially present on the surface of the leaf. However, this hypothesis does not preclude the foliar entrance of endophytic microorganisms, which was already shown experimentally.136,545 Finally, fungi belonging to the Clavicipitaceae family, including Epichloë spp., are mostly transmitted vertically via seeds, and they can colonize the host plant systemically.546

Different plant species and varieties present different physical and chemical characteristics, including root exudation patterns.340,547 Thus, genetically related plants seem to host more similar bacterial endophyte communities,44,548–551 although microbiota diversification does not depend on host phylogenetic distance exclusively.51 In addition, different plant tissues can also harbor distinct endophytic communities, but the factors driving the establishment of the distribution patterns are not clear.37,543 In spite of the fact that root exudates influence microbial communities in the rhizosphere,85 the root endophyte communities can differ significantly from those in the rhizosphere environment,552 showing the selective recruitment of beneficial microbes.

The obligate endophytes in the Clavicipitaceae family and the endophytic PGPMs are the most frequently studied endophytes, and the literature provides some examples of the chemical signaling involved in the plant colonization process by these endophytic microbes. For example, the plant A. thaliana secretes L-malic acid (111, Chart 9) and activates the chemotaxis mobility of B. subtilis, attracting this beneficial rhizobacterium through an enantiomeric-dependent response.58 Dedicated B. subtilis chemotaxis receptors play important roles in the efficient colonization of plants in natural environments.553B. subtilis has been reported to trigger ISR (induced systemic resistance) and promote plant growth and protection from fungal infection.554 Accordingly, the root secretion of 111 was induced by the foliar pathogen Pseudomonas syringae pv. tomato.58 The foliar treatment of A. thaliana with MAMPs, such as flagellin 22 and the pathogen-derived phytotoxin coronatine (37, Chart 4), also elicited 111 secretion in roots to attract B. subtilis.555 Elevated levels of 111 promote binding and biofilm formation in B. subtilis on plant roots,58 a well-established requirement for long-term colonization.553 In addition, the pathogen P. syringae pv. tomato induces root ALMT1 (aluminum-activated malate transporter family) expression in A. thaliana. Interestingly, this ALMT1 expression is independent of B. subtilis, but it is a positive regulator of B. subtilis root colonization.556,557 Other genes are involved in bacterial recruitment,557 indicating that the establishment of interactions between PGPR B. subtilis and the plant host is a complex phenomenon regulated by multiple genetic components.556 Furthermore, B. subtilis triggers plant responses but also suppresses defense-related gene expression in A. thaliana roots, including genes involved in the biosynthesis of the phytoanticipins known as glucosinolates.248,255 MAMPs activate glucosinolates,224 which in turn reduce the induction of the JA pathway, whereas they increase the levels of SA (2, Chart 4).558 Thus, the inhibition of glucosinolate biosynthesis by B. subtilis enables efficient root colonization and establishment of rhizosphere microbial communities.557

The role of organic acids present in banana root exudates during the colonization of the Bacillus amyloliquefaciens PGPR strain was also investigated.559 Oxalic acid (112), fumaric acid (113) and malic acid (111) (Chart 9) induced chemotaxis and biofilm formation, but 111 showed the greatest chemotaxis response whereas 113 significantly induced biofilm formation.559 Similarly, the organic acids secreted by watermelon roots such as citric acid (114, Chart 9) and 111 significantly induced Paenibacillus polymyxa motility. The maximum motility occurred with 111, while 112 was the least effective.560 Secreted 111 was the preferred carbon source for B. subtilis,561,562 and in fact, this was the only signaling molecule in tomato root exudates that regulated root colonization and biofilm formation by B. subtilis.561

Studies on B. amyloliquefaciens isolated from cucumber and B. subtilis from banana rhizospheres were also performed. The chemotaxis response and effects on biofilm formation were assessed for both microbial strains in response to root exudates and their organic acid components separately. Fumaric acid (113) was detected exclusively in banana root exudates while citric acid (114) was only detected in cucumber exudates. Compound 113 possessed significant roles in both chemotaxis and biofilm formation of B. subtilis, while only the effects on biofilm formation but not chemotaxis by B. amyloliquefaciens were observed. However, 114 attracted and induced the biofilm formation of B. amyloliquefaciens, whereas only the chemotaxis response but not biofilm formation was induced in B. subtilis. The authors concluded that root exudate components may drive the colonization of preferential PGPR strains.116 In addition, the role of cucumber infection with Fusarium oxysporum f. sp. cucumerinum J. H. Owen in the colonization of PGPR B. amyloliquefaciens was investigated. Pathogen infection had a positive effect on root colonization and increased the root secretion of 114 and 113, enhancing the chemo-attraction of beneficial microorganisms to the roots of infected cucumbers and biofilm formation.56 In fact, 113 had not been detected previously in the root exudates of non-infected cucumber.116 Together with 111, 114 is a suitable carbon source for many microorganisms.557 Not only root exudates but also the polysaccharides present in plant cell walls substantially stimulate the biofilm formation of PGPR Bacillus strains,563 also impacting root-microbe colonization.

The PGPB P. putida is recruited to maize roots by chemotaxis toward the benzoxazinoid DIMBOA (39, Chart 3), the primary benzoxazinoid found in maize root exudates.60 As described before, this compound also possesses antimicrobial and allelochemical activities. In addition, inoculating rice seedlings with the flavonoids quercetin (91) and daidzein (102) (Chart 8) was found to improve the endophytic colonization ability of Serratia sp. significantly. However, some plant growth hormones were reported to impair Serratia sp. colonization.564

3.2.2. Modulation of plant immunity during endophytic/epiphytic colonization. The modulation of host immunity by PGPMs has been reviewed in detail.14 Similar to rhizobia and mycorrhiza, beneficial microbes such as PGPR, which often grow endophytically inside the roots, should also escape the host's defense and successfully colonize plants.14 A way to avoid inducing the immune response is to reversibly switch between colonies with different morphologies, a bacterial adaptive process known as phenotypic or phase variation.565,566 For example, the PGPR Pseudomonas brassicacearum shows two distinct morphological variants.567 In one phase, P. brassicacearum produces significantly lower amounts of flagellin to mask recognition by the host during the colonization of new roots. Flagellin is degraded by an alkaline protease (AprA) that is expressed during this phase.567 In fact, P. aeruginosa excretes AprA to evade host immune activation in both plants and mammals.226 Thus, the phenotypic variation strategy has advantages for some bacteria during host colonization.

Nevertheless, beneficial microbes such as the PGPR Pseudomonas fluorescens260 and the PGPF Piriformospora indica568 can be recognized by the root immune system through their MAMPs, eliciting the MTI response at an initial stage. However, as with pathogens, beneficial microbes also suppress the MTI through the production of effector molecules.260P. fluorescens secretes effectors that trigger the HR (hypersensitive response) in Nicotiana clevelandii. However, some T3SS-secreted effectors were capable of suppressing plant immune responses such as the HR and the production of ROS (reactive oxygen species).569 ROS have been suggested to play a crucial role in different steps of the interplay between endophytes and their host plants, and the disruption of this signaling can lead to a breakdown in their mutualistic interaction.514 Therefore, PGPR effectors that are delivered via T3SS may either trigger or suppress some plant defense responses, and thus their significance in PGPR remains far from clear.14 LPS (lipopolysaccharides) and EPS (exopolysaccharides) may also suppress MTI during early stages of interaction between PGPR and host plants, similar to rhizobia.14

PGPMs also modulate host immune responses by interfering with the ET signaling pathway. P. fluorescens significantly reduces the expression of some ET-responsive genes570 and secretes the enzyme ACC deaminase, which is responsible for degrading the ET precursor.327,571 ET (29, Chart 4) is also important for regulating root colonization by beneficial endophytic fungi. For example, the plant activation of ET defense responses reduced root colonization by the PGPF P. indica.572 Additionally, the structuring of the bacterial endophyte community in Nicotiana attenuate roots is also dependent on ET homeostasis.573 The activation of the JA pathway has been reported during plant immunity modulation by beneficial microbes. P. indica induced the JA signaling pathway to suppress defense responses. However, the suppression of the SA signaling pathway through the production of phytohormone-like secondary metabolites is a strategy that is also used by PGPMs.14 It was reported that the SA pathway impairs the colonization of Arabidopsis roots by P. indica.568 Microorganisms also synthesize the auxin IAA (10, Chart 4) and can induce its biosynthesis in plants.37,425,574,575 This auxin has been demonstrated to negatively cross-communicate with the SA signaling pathway.14 Thus, the microbial production of 10 may increase the plant colonization efficiency of endophytes.340

3.2.3. Common secondary metabolites produced by plants and endophytic microorganisms. The examples of plant secondary metabolites that are also biosynthesized by associated microbes have increased (Chart 10),576 raising intriguing questions about chemical crosstalk, horizontal gene transfer, shared biosynthetic pathways, ecological significance, and co-evolution between the partners.
image file: c7cs00343a-c10.tif
Chart 10 Chemical structures of plant secondary metabolites also biosynthesized by resident endophytes, and maytansine.

The remarkable discovery of the endophytic fungus Taxomyces andreanae, which was isolated from the bark of the Pacific yew Taxus brevifolia and which also produces paclitaxel (Taxolenti®) (115, Chart 10),577 encouraged subsequent multidisciplinary efforts to address these questions in relation to different plant–microbe interactions. Paclitaxel (115) was further identified at low levels in different endophytic fungi from the Taxus species and other unrelated plants. Taxol® (115) is a microtubule-stabilizing blockbuster anticancer drug, and the use of endophyte biotechnology for its production has not been achieved yet.578 The highly modified diterpene 115 also presents antifungal activity.579 However, the reason why endophytes from different plants produce 115 has been an absorbing question that was recently addressed by Soliman and colleagues using a neat series of experiments.580 The authors observed that Taxus plants present persistent cracks in their bark as a result of growing branches, creating suitable environments for pathogen entry. Despite its antifungal activity, Taxus plants are unlikely to use their own paclitaxel (115) as a general defense strategy, since its inhibitory activity against cell division would prevent plant growth at the cracks. The paclitaxel-producing endophytic fungus Paraconiothyrium SSM001 and paclitaxel itself showed antifungal activity against wood-decaying fungi. It was demonstrated that the SSM001 fungus migrates to branch cracks in Yew trees and accumulates paclitaxel in hydrophobic bodies, which are released from hyphae by exocytosis in response to chemical elicitors that are unleashed by the pathogens, constituting a localized and refined defense strategy. The authors argue that Taxus plants and paclitaxel-producing endophytes might have shared common precursors for diterpene production and compatible signaling pathways.580

Camptothecin (116, Chart 10) and its structurally related pentacyclic quinolone alkaloids are plant-derived antineoplastic agents that target the enzyme DNA topoisomerase-I and they are also produced by endophytic fungi.581–583 However, attenuation in the production of these alkaloids by the endophytic fungus Fusarium solani was observed after successive generations of subcultures.582 Further studies revealed that F. solani requires the host plant's strictosidine synthase enzyme to complete 116 biosynthesis, explaining the decrease in alkaloid production by the fungus after several generations.584 Interestingly, F. solani was demonstrated to develop self-resistance against 116 toxicity by modifying the amino acid sequence of its own topoisomerase-I.585 The molecular and chemical signals that control this intimate communication between both partners still deserve further investigation.

Podophyllotoxin (117, Chart 10) is a precursor of the anticancer drugs etoposide and teniposide, all of which target topoisomerase. The endophytic fungus Trametes hirsuta, which was isolated from the rhizomes of Podophyllum hexandrum, was found to produce the plant-derived lignan podophyllotoxin (117) and other related aryl tetralin lignans.586 Different fungal endophytes from other podophyllotoxin-producing plants were subsequently found to also produce 117 and its analogs.587–589 The authors claim that the consistent production of lignans by these endophytes supports the theory that during evolution, microorganisms developed the ability to compete and survive in association with medicinal plants by acquiring the apparatus to biosynthesize similar compounds and develop a tolerance to high levels of plant secondary metabolites.589

The bisindole alkaloids vincristine (118, Chart 10) and vinblastine (119, Chart 10) are important drugs that are used in cancer chemotherapy, and they are biosynthesized by the plant Catharanthus roseus. Both alkaloids were isolated from a culture of F. oxysporum, an endophytic fungus isolated from the leaves of C. roseus. The vincristine (118) and vinblastine (119) yields in media supplemented with tryptophan and geraniol were higher than those obtained using a plant-based method.590 Further studies showed that two bacterial endophytes, Staphylococcus sciuri and Micrococcus sp., enhanced both C. roseus growth and vindoline (120, Chart 10) and other related alkaloid contents.591 More recently, it was shown that the fungal endophytes Curvularia sp. CATDLF5 and Choanephora infundibulifera CATDLF6, which were isolated from the leaves of C. roseus, increased the vindoline (120) content by 229–403% in endophyte-inoculated plants by upregulating the expression of genes involved in the terpene indole-alkaloid biosynthetic pathway.592

Hypericin (121, Chart 10) is a naphtodianthrone commonly found in plants of the Hypericum genus, which is used in traditional medicine. The endophytic fungus Thielavia subthermophilia, which was isolated from the stems of Hypericum perforatum (St. John's Wort), was found to produce hypericin (121) and emodin (122, Chart 10) in axenic culture.593 Subsequent studies revealed that the hyp-1 gene was absent in the fungus, indicating that different biosynthetic pathways or different molecular mechanisms are operating in the endophyte and its host plant.594 Hypericin (121) is synthesized and accumulated in the dark glands present in flowers and leaves, acting as a plant-chemical defense against microbial and insect pathogens in the above-ground tissues.594,595 Kusari and colleagues594 proposed that endophyte-derived 121 and 122 could act as stem-localized chemical defenses for the host plant.

Huperzine A (123, Chart 10) is an alkaloid with acetylcholinesterase inhibitory activity that was first isolated from the medicinal Chinese plant Huperzia serrata. The endophytic fungus Shiraia sp. Slf14 that was isolated from H. serrata also produces low yields of 123.596 The same research group later found that the addition of some elicitors to the fungal culture, such as extract from the host plant and L-lysine (95, a plausible precursor in the alkaloid biosynthesis), enhanced 123 production.597 The authors stated that huperzine (123) production is regulated by plant products or other small molecules, but the molecular mechanism of this signaling remains unclear. Other endophytic fungi from H. serrata also produced 123, and ethanol and methanol improved the alkaloid production by the endophyte Colletotrichum gloeosporioides ES026.598 Again, the precise mechanisms by which the alcohols promote these effects remain to be investigated.

The ansamycin known as maytansine (124, Chart 10) targets microtubules and is used to treat mammary carcinoma cells as an antibody conjugate.599 Maytansine (124) was first found in low yields in celastraceous plants, including Putterlickia verrucosa and Maytenus serrata.600 However, its polyketide structure is unusual for plant metabolites, resembling compounds that are commonly produced by eubacteria.576 More recently, 124 was found to be biosynthesized by the endophytic bacterial community of the roots of Putterlickia plants, and its accumulation in the root cortex was evidenced by MALDI-imaging-HRMS.599 The starter unit for biosynthesizing ansamycins is 3-amino-5-hydroxybenzoic acid (AHBA), and the presence of an AHBA synthase gene in the root endophytic communities was confirmed. The same gene is absent in sterile plants, reinforcing the bacterial production of the compound. In fact, there was earlier evidence that endophytes were absent in sterile Putterlickia plant cell cultures that do not produce 124.601,602 The mechanisms that control this intricate interaction between plants and bacterial consortia remain to be deciphered.

Other plant metabolites have also been identified in endophytic cultures. Azadirachtin (125, Chart 10) is a tetranortriterpenoid insecticide that was isolated from the neem tree Azadirachta indica and was also identified in the associated endophytic fungus Eupenicillium parvum.603 Betulinic acid (126, Chart 10) was recently identified as one of the most active compounds in the plant Diospyros carbonaria and its endophytic fungus Phomopsis sp. by using a dengue replicon virus-cell-based assay,604 creating opportunities for further study of the chemical signaling involved in this plant–fungus interaction. Resveratrol (127, Chart 10) occurs in grapes, berries, peanuts and other medicinal plants, and it is well known for its health benefits. Resveratrol (127) has been identified in a variety of endophytic fungal strains from different plants and fruits.605 Unlike other fungal isolates, Alternaria sp. MG1 showed a stable production of 127 during sub-culturing. The biosynthesis of flavolignans such as silybin A (128, Chart 10) by Aspergillus iizukae, which was isolated as an endophyte from Silybum marianum (Milk Thistle), was also reported.606 The production of flavolignans decreased after sub-culturing, as observed in most cases of plant-metabolite production by endophytes. Interestingly, the addition of autoclaved Milk Thistle leaves to the growth media stimulated the fungal biosynthesis of flavolignans, showing that plant signals may be involved in triggering the endophyte biosynthetic machinery.606

Endophytes from Artemisia annua have not shown the ability to biosynthesize the antimalarial drug artemisinin (129, Chart 3) as their host plant. However, the addition of host fungal (Colletotrichum sp.) and actinobacterial (Pseudonocardia sp.) endophytes to plant tissue cultures of A. annua enhanced the production of the sesquiterpene lactone endoperoxide.607,608 It has been verified that Pseudonocardia sp. upregulates the expression of plant genes involved in 129 biosynthesis.608 Artemisinin (129) is a phytoalexin with allelopathic effects that protects plants against herbivores and microbial pathogens.609,610 Therefore, endophytes could improve plant defenses by stimulating 129 production.

The examples highlighted here clearly show that the endophytic community might have evolved the ability to produce secondary metabolites similar to those of their host plants, or they can even impact the biosynthesis of plant metabolites, providing perspectives for biotechnological applications. However, the molecular mechanisms involved in triggering similar chemical responses in both symbiotic partners remain to be elucidated in most interactions.611 This is a crucial issue not only for the sustainable production of plant metabolites by endophyte biotechnology but also for understanding the evolution between the symbiotic partners.

3.3. Chemical signaling in pathogenesis

Based on scientific and economic importance, interesting rankings for pathogens were created, resulting in a series of publications about the top 10 plant-parasitic nematodes,612 plant viruses,613 fungal pathogens,614 and pathogenic bacteria in molecular plant pathology.615 These rankings have provided a general idea about the most studied pathogens whose contribution to the understanding of phytopathogenic processes has been valuable. However, the authors of these papers emphasized that the importance and priorities can vary locally across continents and disciplines.612–615 The fungus that received the most votes corresponded to Magnaporthe oryzae due to its devastating effects on rice crops worldwide as well as its importance as a model for plant–pathogen interactions.614 The strongest appearance in the bacterial ranking was for P. syringae due to its huge impact on researchers understanding of microbial pathogenicity as well as on food production.615 The first item in the virus ranking corresponded to tobacco mosaic virus (TMV) because it has been a model system for more than 110 years and for the need to understand how to control TMV-induced disease in tobacco.613 Finally, the most plant parasite votes from the rankings were given to root-knot nematodes (Meloidogyne spp.), which are distributed globally and are able to parasitize almost every species of vascular plants.612 These papers highlight the wide range of pathogenic organisms as well as the trend in the study of plant pathogens that may change according to ongoing research and future interests. Thus, as discussed below, recent findings in the chemical signaling involved in pathogenesis from plant–microbe systems have contributed to an understanding of plant disease processes.

According to their lifestyle, plant pathogens can be classified as necrotrophs (that destroy host cells and feed on their contents) and biotrophs (that derive nutrients from living host tissues).301 However, they can change their states during their life cycles, as observed in hemibiotrophs (biotrophs that can switch to necrotrophs); therefore, classification according to their nutritional status is often challenging.616 No matter what type of life cycle they have, pathogens colonize their hosts to access nutrients. To guarantee this colonization, pathogens may modify their metabolic machinery according to the nutrient supply in a specific niche.617 Some pathogens are limited to a small host range and produce toxic compounds that display differential activities to their host plants. Those molecules are known as host-selective toxins. Filamentous fungi such as Sclerotinia sclerotiorum (white mold) and B. cinerea (gray mold) have a broad host range, encompassing over 200 plant species, whereas Alternaria spp. seem to be more selective.276,618

Several factors, such as the invasion mechanisms, effectors, species, and others, are involved in pathogenesis (Fig. 5), making it a very complex process.619–621 For example, pathogenesis by oomycetes and fungi includes the dispersal of the spore near the host, attachment/adhesion to the host, host recognition, germination, penetration of the host, infection, growth inside the plant, lesion development in the host and reproduction/sporulation.619 The next topics will cover examples of the chemical signaling behind several steps of plant–pathogen symbiosis.

image file: c7cs00343a-f5.tif
Fig. 5 General overview of chemical signaling involved in pathogenesis. PSK (53) signaling has been directly involved in disease susceptibility during plant development. This finding suggests that other chemical signaling pathways may be involved in pathogenesis. During penetration by pathogenic microorganisms, molecules such as coronatine (37) are involved, and it interferes with the stomata closing process; or eremophilene derivatives (e.g., 147), which are involved in regulating the appressorium, an infectious structure for fungal adherence to host surfaces. Once inside the host, small molecules (e.g., 136) and protein effectors play several roles as virulence factors by inducing cell death, interfering with plant metabolic pathways, and even modulating the plant immune system. In addition, microbial communication seems to be an important factor in disease because members of the plant microbiome, not only pathogens but also endophytes and epiphytes, can modulate pathogenic behavior. QS molecules such as AHLs (e.g., 11) are mediators of this interspecies communication and contribute to plant infection and disease.
3.3.1. Penetration of pathogens into the host. The process of plant infection by bacteria starts with the ability to survive on the plant surface, followed by biofilm formation, then migration across plant surfaces to apoplastic entry sites, production and the release of phytotoxins to bypass stomatal closure, damage plant tissue by extracellular enzyme secretion, and the secretion of phytotoxins to manipulate plant physiology, metabolism and the modulation of immune responses.621 Chemical signaling seems to occur at every step, and it has been studied in some cases. Because the pathogenic process starts with microorganism survival on external plant surfaces, bacteria need to develop mechanisms to guarantee their epiphytic prosperity.621 The decision-making process for bacteria to thrive on the plant surface or bypass the leaf epidermis and consequently colonize the vascular system is mediated by small molecule-based signaling pathways.621 In P. syringae, QS (quorum sensing) and second messenger pathways are mediated by AHLs (acyl homoserine lactones) and cdG (cyclic di-guanosine 3′,5′-monophosphate, 130, Chart 1), respectively.622–625 Interestingly, 3′-O-C6-HSL (AI-1, 11, Chart 2) from the phytopathogen P. syringae negatively regulates the genes involved in the virulence features and represses bacterial motility.624 The involvement of 130 in several cell processes, including virulence in various organisms, has been comprehensively reviewed.626 Recently, it was demonstrated that 130 plays important roles in mediating infections by plant-associated Pseudomonas strains as well as in immune system evasion.625 High levels of cdG (130) reduce the extracellular levels of flagellin, the structural unit of flagellum filaments that elicits PTI (pattern-triggered immunity) in plants, demonstrating the direct link between cdG-regulated flagella synthesis and the evasion of plant immunity.625 Flagellar motility is also important for the migration process into the apoplast, which is therefore recognized as a critical component for plant pathogenicity. However, the chemical signaling that regulates this process in planta is unclear and needs further investigation.621

An entry point for pathogenic bacteria is through the stomata, and secondary metabolites such as the phytotoxins coronatine (37, Chart 4)230,231 and syringolin A (38, Chart 11)232 from P. syringae may interfere with the stomatal closure process that occurs during plant defense. Other strategies to enter the apoplast include penetration through wounds on the plant epidermis caused by microbially secreted enzymes and proteins that damage cells,621 such as ice-nucleating agents (INAs), which cause frost damage and enable pathogens to enter plant tissue.621P. syringae is also known as a biological ice-nucleating agent due to its ability to produce proteins, such as inaZ,627 causing water to freeze, damaging cell walls and consequently invading plant tissues.621,628 The molecular mechanisms by which this phenomenon occurs are under investigation; however, it was recently demonstrated that P. syringae effectively arranges vicinal molecules of water, which may occur through active inaZ sites.629 Once inside the plant tissues, pathogenic bacteria produce toxins with several purposes. For instance, lipopeptide toxins such as syringomycins (e.g., syringomycin E, 131) and syringopeptins (e.g., syringopeptin 25A, 132) (Chart 12) from P. syringae630 cause direct damage to plant cells.621 Other peptide toxins known as antimetabolite toxins, such as tabtoxin (133) and phaseolotoxin (134) (Chart 11),631 can interfere with nitrogen metabolism and the biosynthesis of amino acids mostly belonging to the urea cycle.631

image file: c7cs00343a-c11.tif
Chart 11 Other toxins and virulence factors produced by pathogens.

image file: c7cs00343a-c12.tif
Chart 12 Microbial cyclic lipopeptides with toxic effects on plants and challenging microbes.

Unlike bacteria, the necrotrophic fungi M. grisea and B. cinerea, which are closely related, develop appressoria to colonize plant tissues.618 The appressorium is an infectious structure that is formed prior to host penetration, and it is necessary for fungal adherence to host surfaces and for infection by many pathogenic fungi.632 These structures may exert physical pressure on the host tissue and secrete enzymes to breach the plant surfaces.618 Both M. grisea and B. cinerea share the membrane protein tetraspanin, which is required for the appressorium-mediated penetration of host plants. However, B. cinerea primarily produces degradation enzymes for entering the host rather than using physical pressure. In addition, this fungus causes an oxidative burst by producing ROS.276,633 Pathogenic fungi also produce toxins to damage cells, and some examples will be discussed later.

3.3.2. Modulation of the plant immune responses by pathogens. The dynamic cellular processes involved in plant–microbe interactions, in which plant cells attempt to control cellular trafficking pathways and divert them toward defensive processes while pathogens attempt to hijack them to promote parasitism, have been comprehensively reviewed by W. Underwood.634 In addition, plant defense mechanisms against pathogens may differ in the above- and below-ground tissues including, for instance, the production of different arrays of antimicrobial compounds in the leaves versus the roots.91 In fact, plants may have several defense responses that show changes in primary and secondary metabolism depending on the challenging pathogen.635 The involvement of signaling metabolites, such as 1-methyltryptophan (135), pipecolic acid (136) and azelaic acid (137) (Chart 9), was suggested during tomato (Solanum lycopersicum) plant infection with the pathogens B. cinerea and P. syringae.635 An increase in 135 was observed as a consequence of P. syringae infection, although the biological origin of this metabolite could not be established at first.635 Interestingly, plant treatment with 135 reduced the infection incidence of B. cinerea and P. syringae, indicating that this compound acts as an inducer of plant protection; however, the plant response mechanism has not been deciphered yet.635 An accumulation of 136 was also observed upon B. cinerea and P. syringae infection, suggesting a role in defense against necrotrophs.635 Its role as an endogenous mediator of defense priming was previously established.636,637 Similar results in the S. lycopersicum plant635 demonstrated that 136 also orchestrates immune responses in plant species other than Arabidopsis.636 Compound 137 is a phloem-mobile signal that is also implicated in SAR (systemic acquired resistance).637,638 Its levels were increased up to five-fold during tomato plant infections with both pathogens B. cinerea and P. syringae.635 In addition to 137, lipids may also play several roles in plant–microbe interactions, and they have been reviewed elsewhere.639

For all the above cited examples of symbiosis in this review, the plant responses must be suppressed to facilitate the infection and effector proteins secreted by plant pathogens, which may play a role by interfering in the signal pathways involved in host resistance.640 In addition to the production of secondary metabolites, effector proteins are also involved in pathogenesis and are injected into plant cells by specialized secretion systems, which have been classified into at least six different classes (types I–VI).641 Most Gram-negative plant pathogenic bacteria depend on T3SS,642 although this system is not exclusively linked to pathogenicity.643 The major role assigned to T3SS-secreted effectors was the suppression of plant immunity; however, their participation in other processes of pathogenic bacteria, such as the manipulation of plant hormone signaling pathways and alterations in the cell structure, has been established.644 Curiously, a negative correlation between syringomycin-like phytotoxin production and the secretion of T3SS effectors has been suggested in P. syringae.645 Another important target for pathogens is the primary protein degradation system in eukaryotic cells, or UPS (ubiquitin-26S proteasome degradation system),646 which is involved in the degradation of signaling components belonging to different plant hormone pathways, such as SA, JA and ET.647 Because UPS cooperates in the regulatory pathways that control most of the plant life processes, the production of proteasome inhibitors, such as syringolin A (38, Chart 11), is a very effective virulence strategy for plant pathogens.646

Suggesting the role of effector proteins in the colonization ability of fungal pathogens, establishing an interaction with the host and even promoting virulence remain challenging.640,648,649 Secretome analyses of S. sclerotiorum and B. cinerea revealed over 400 secreted proteins, including nearly 80 virulence factor candidates,650,651 indicating that chemical interactions between these pathogens and their host may be even more complex than previously thought. According to Selin and collaborators,648 approximately 83 effector proteins have been characterized from crop-infecting fungi and oomycetes, although their role in virulence remains unknown for the most part.648 One of the best characterized oomycetes is P. infestans, which is responsible for late blight disease in potato (Solanum tuberosum) and tomato (S. lycopersicum).652,653 The secretion and delivery of two effectors, cytoplasmic effector Pi04314654 and the apoplastic effector EPIC1 from P. infestans, have recently been described.655 The authors demonstrated that the two effectors are secreted from the haustoria (specialized structures for nutrient transport in the host–parasite interface),656–658 although they follow different secretion pathways. EPIC1 followed the endoplasmic reticulum to the Golgi-secretion system, while Pi04314 was not dependent on Golgi-mediated secretion.655 Future work will be necessary to demonstrate if this is a general rule for fungal and oomycete plant pathogens,655 because distinct secretion systems are fundamental for pathogen invasion.659 Therefore, the secretion of both apoplastic and cytoplasmic effectors from haustoria during infection reveals the involvement of a haustorial interface for pathogen and plant host interaction.655 Fungal and oomycete effector translocation is still poorly understood, and the current knowledge in the field has been reviewed recently.660 A better understanding of plant–pathogen interactions can be reached with large-scale approaches such as proteomics.648 In a recent study, it was demonstrated that the fungus F. oxysporum secretes SIX proteins into the xylem during the colonization of tomato vessels, some of them required for virulence.661 That study suggested that SIX effectors may play a role in overcoming plant physiological adaptations, enabling fungal infection and spreading, although further studies are necessary to reveal the identity of the signaling pathways with which they interfere.661 Effectors of the maize biotrophic pathogen Ustilago maydis are among the few that have been extensively studied.648 Five effector proteins (Pep1, Pit2, Cmu1, Tin2 and See1) have been fully characterized and virulence-related functions have been suggested.648 For example, Pep1 seems to be involved in triggering the HR (hypersensitive response);662 Pit2 is required for inducting an SA-dependent defense;663 Cmu1 has been involved in lowering the SA (2) levels, favoring U. maydis colonization;664,665 Tin2 is responsible for inducing plant anthocyanin [e.g., cyanidin-3-glucoside (138), Chart 8] production and is involved in virulence;666,667 and the See1 effector seems to modulate immune responses in leaf cells.668 In the case of the hemibiotrophic pathogen M. oryzae, three effector proteins have been well characterized, with two of them (SPL1 and AvrPiz-t) being involved in pathogenicity.648 SPL1 may play a role by suppressing the chitin-triggered defense response, which is mediated by chitin interactions with the plant receptor CEBiP (chitin elicitor binding protein),669 and AvrPiz-t degrades APIP6 (AvrPiz-t Interacting Protein 6), which is involved in PTI, consequently leading to ROS reduction and increasing rice plant susceptibility to M. oryzae.670

Hormone crosstalk provides the plant with a powerful tool to regulate its immune system and can also be a target for pathogens, which manipulate it for their own benefit.240 Several strategies to suppress host defenses, including the hormonal manipulation of JA (3),205 the production of the JA-Ile-mimicry molecule coronatine (37),231 and the degradation of SA (2) (Chart 4) that increase pathogen virulence on plants, have been reported.234

3.3.3. Virulence factors. Elucidating the mechanisms that pathogens use to avoid and suppress host immunity was an early goal of molecular plant pathology.671 At present, advances in the field have helped to reveal the virulence factors of some plant diseases. For example, the pathogen Erwinia amylovora, which is responsible for fire blight disease in Rosaceae species, requires two major virulence determinants to cause disease, namely, the EPS amylovoran and the Hrp T3SS (T3SS encoded by hrp genes).672 Amylovoran is a pentasaccharide-repeating unit containing four subunits of galactose and one unit of glucuronic acid, and it is important for biofilm formation.672 Hrp T3SS is fundamental for delivering effector proteins belonging to the AvrE family, whose biological function is not completely understood.672 Bacterial wilt is one of the most destructive bacterial diseases of solanaceous species, and it is caused by R. solanacearum. The virulence factors of R. solanacearum include EPSs, cell wall-degrading enzymes, motility, and the ability to use nitrate and T3SS.673 Enzymes are among the virulence factors in plant disease. The contribution of extracellular fungal proteases in pathogenic mechanisms has recently been reviewed, highlighting their importance as molecular markers for phytopathogenicity.674

Recently discovered virulence factors also include secondary metabolites. Tentoxin (139, Chart 11), a non-ribosomal cyclic tetrapeptide from Cochliobolus miyabeanus, was discovered as the causal agent of brown spot disease in rice.675 It was demonstrated that 139 was not necessary for pathogenesis, but it contributes to the disease severity at later phases.675 That study also suggested that C. miyabeanus relies on an array of non-specific virulence factors because in addition to 139 production, ophiobolins (e.g., ophiobolin A, 140, Chart 11), sesterterpenoid non-host-specific phytotoxins, are also produced by this necrotrophic pathogen.675 The involvement of the fungal toxin cercosporin (141, Chart 11) from Pseudocercosporella capsellae in the white leaf spot disease of Brassicaceae species was also recently demonstrated.676 A “toxin-like” and “effector-like” small protein was also identified in S. sclerotiorum, and it is essential for the full virulence of this necrotrophic phytopathogen.677 The cysteine-rich secreted protein SsSSVP1 was able to induce plant cell death, which is consistent with necrotrophic behavior.677 In addition, this small protein may attack a well-conserved component of the mitochondrial respiratory chain in plants, which is consistent with the broad host range of S. sclerotiorum.677 Fungal secondary metabolites can be chemically diverse, with structural families belonging to polyketides, terpenoids, shikimic acid derivatives, and non-ribosomal peptides, with a wide range of biological activities.20 In addition, some of the metabolites produced by phytopathogenic fungi can act as phytotoxins, and they can be further classified as host-selective toxins and non-host selective toxins, as mentioned earlier.20,678 The involvement of secondary metabolites in several plant diseases has recently been reviewed, highlighting the chemical signaling mediation in pathogenesis.20 For example, the blast fungus M. grisea is a species complex that causes disease in approximately 50 grass and sedge species. The appressorium formation in M. grisea is stimulated by fatty acid derivatives but is also self-regulated by phytotoxins such as pyriculol (142, Chart 11), for which new analogs have been reported.679 Other fungi can produce non-phytotoxic inhibitors of conidial germination and appressorium formation in M. grisea such as flaviolin (143), tenuazonic acid (144) and glisoprenins (e.g., glisoprenin C, 145) (Chart 11).680 Recently, it was demonstrated that a new family of fungal metabolites with an eremophilene skeleton, such as (+)-4-epi-eremophil-9-en-2α,11-diol (146), (+)-4-epi-eremophil-9-en-1α,2α,11-triol (147) and (+)-4-epi-eremophil-9-en-2α,8β,11-triol (148) (Chart 11), were involved in the conidiation process and regulation of complex appressoria in B. cinerea.681 This fungus secretes nonspecific phytotoxins within a large range of plants. The best-studied compound is the sesquiterpene botrydial (149, Chart 11), which is produced during plant infection and induces cell collapse, facilitating penetration into the host plant.633 The virulence of certain Botrytis strains might rely on 149, whereas others can produce additional toxins, such as botcinolide (150, Chart 11).618 In addition to these toxins, oxalic acid (112, Chart 9) seems to be required for pathogenicity.682 The role of 112 in species of the Sclerotiniaceae family has been investigated. In S. sclerotiorum, for instance, the exogenous acidification of plant tissues restored virulence in mutants that were unable to produce 112, suggesting that a low pH, rather than a specific acidic molecule, is important for virulence. Alternatively, B. cinerea was found to produce citric (114) and succinic (151) acids (Chart 9) during the colonization of sunflowers.276,683 As mentioned earlier, B. cinerea is the causal agent of the widespread gray mold; however, it may be beneficial by causing noble rot in grape berries, which are used to produce sweet wines.614 These findings show how chemical signaling between plants and their associated microbes is complex.

An additional review covering grapevine trunk diseases (Eutypa dieback, esca and Botryosphaeria dieback) shows the complexity of plant diseases and highlights that several factors, such as secondary metabolites, environmental conditions or even microbiological equilibrium, may influence the progress of a disease.684 During the investigation of Eutypa dieback disease (or eutypiosis), which is caused by the pathogenic fungus Eutypa lata, several fungal secondary metabolites were characterized.685 The primary phytotoxin, eutypine (152, Chart 11), seems to uncouple the mitochondrial oxidation phosphorylation and decrease the ADP/O ratio in grapevine cells by increasing proton leaks through a cyclic protonophore mechanism.686 However, several structurally related compounds are produced by the fungus, and the fungal phytotoxicity may result from different levels of toxicity and molecular targets of the individual chemical entities.684 The structural relationship of a phytotoxin and pathogenesis has been illustrated in grapevines. The production of regiolone (153) instead of isosclerone (154) (Chart 11) may be part of a specialization process of Botrytis fabae to become more virulent than B. cinerea in faba bean.165,687 In addition to that, other structural features can be associated with phytotoxicity, such as the anthracenone carbon skeleton and the functionalization and ring conformation present in altersolanol A (155, Chart 11).165,688 For a comprehensive review on secondary metabolites from fungus–plant interactions covering a wide range of chemical structures, see Pustztahelyi et al.20

3.3.4. Plant–pathogen symbiosis: a complex process. Although recent findings and reviews about general steps of plant–pathogen interactions have been described here, further studies are needed to understand pathogen–plant interactions completely because variations can be observed on a case-by-case basis. For example, a first description of a plant pathogenic vascular bacterium that invaded non-vascular plant tissues was reported.689 Based on microscopic observations, Xanthomonas albilineans, a bacterium with a reduced genome and the causal agent of the sugarcane leaf scald, was shown to move within the xylem. It is able to invade intact parenchymal cells as well as other non-vascular cells. At the early stages of invasion, the bacterium is only observed in the xylem, but during the progress of the disease, X. albilineans spreads out and is observed in other plant cells, such as phloem cells, vascular parenchyma cells and several non-vascular cells. This is a remarkable discovery since this characteristic behavior has not been previously described in any pathogenic bacterium, and it contradicts the current knowledge regarding the habitat of plant pathogenic bacteria.689 Interestingly, the mechanisms used by X. albilineans to leave the xylem and to invade parenchymal cells remain unknown since pathogenicity factors such as albicidin toxin (156, Chart 11), DSF (19, Chart 6), Salmonella pathogenicity island-1 (SPI-1) T3SS and surface polysaccharides are not directly involved in the described phenomenon.689

The investigation of individual pathogens in defined plant models is highly simplified and far from realistic natural contexts, in which pathogenic behavior is modulated by interactions and signaling with other members of the plant microbiome.621 Therefore, more investigations about how pathogens interact and communicate with each other will provide valuable information for this purpose. For example, an interesting study evaluated a host-mediated interaction between Blumeria graminis and Zymoseptoria tritici in a laboratory system that allowed the two pathogens to infect the same host simultaneously.690B. graminis is an obligate biotroph, and a powdery mildew pathogen of wheat; and Z. tritici is a necrotroph that starts as an endophyte and then switches its state to become the causal agent of Septoria tritici blotch. The observed inhibition of B. graminis through pre-infection of wheat by Z. tritici may be explained due to the different host responses to the two diseases. In that case, the authors proposed that yet-unknown early signaling events during the latent phase of the interaction between wheat and the virulent genotype of Z. tritici prior to the necrotic phase resulted in the suppression of B. graminis.690 This is just an early approach to how complex the process of pathogenesis can be in nature. Pathogenic microorganisms involved in plant diseases need to be studied by accounting for possible antagonistic, mutualistic or synergistic interactions that occur among pathogens.691 Because the investigation of plant diseases involving pathogen–pathogen associations is at its beginning, the mechanisms behind these synergistic and/or antagonistic interactions that may involve immune suppression or modulation of phytohormone-based signaling pathways must be explored.691 The influence of nonpathogenic bacteria in plant disease has also been demonstrated. Knots disease, which affects olive trees (Olea europaea), is caused by Pseudomonas savastanoi pv. savastanoi and microbial interactions with nonpathogenic bacteria. It has been suggested as the causative agent of the increased severity of the disease.692,693 Two nonpathogenic bacteria were found to be associated with P. savastanoi, Pantoea agglomerans and Erwinia toletana, which may present either as endophytes or as epiphytes. It was concluded that the three bacterial species produced AHLs that are essential for the virulence of P. savastanoi. Additionally, it was established that E. toletana acted synergistically with P. savastanoi, increasing the severity of the disease. That study suggested that complex interspecies communication processes may be necessary for the formation of the three-membered consortia involved in the olive knot disease.692 A recent study demonstrated the direct involvement of soil bacteria as providers of virulence signals that promoted plant infections by Phytophthora pathogens.694 In this study, it was demonstrated that a Bacillus megaterium strain promoted plant infections by thirteen Phytophthora species. Bacterial exudates also contributed to pathogenic infection, demonstrating the direct involvement of bacterial virulence signals.694 Interestingly, the Phytophthora species are able to produce the universal quorum sensing molecule AI-2 (17, Chart 1) to recruit bacteria.695,696 Then, Phytophthora species establish relationships with soil bacteria that are beneficial for plant infections, because this plant pathogen is present in small populations in nature.694 This study also highlights bacterial metabolites as mediators of intercellular virulence signaling to Phytophthora pathogens,694 although more studies are necessary to characterize those molecules fully.

Genetic variations also play a role in disease during plant–pathogen interactions. Because the loss and gain of genes have been associated with the host range in plant pathogens, the difference in the fungal gene content when comparing two pathogenic fungal siblings, Colletotrichum graminicola and Colletotrichum sublineolum, reflects an adaptation process during the host–pathogen co-evolution.697 Although genetically and morphologically similar, the two pathogenic species are host-specific; C. graminicola causes disease in maize while C. sublineolum infects sorghum.697 In Burkholderia glumae, which is responsible for bacterial panicle blight in rice, a rapid genetic evolution has also been observed, suggesting a pathogen–host interaction that is dependent on environmental factors.698 An additional interesting fact is that the bacterial wilt caused by B. glumae is symptomatically indistinguishable from the same disease caused by R. solanacearum, highlighting the need for further investigation at the molecular level to understand and control the plant disease.698

4. Agricultural benefits of understanding plant–microbe signaling

In addition to its ecological, biological and chemical importance, all the knowledge gathered over the past few decades about plant–microbe symbiosis is also relevant for agricultural purposes. As shown in this review, microbes contribute greatly to plant-host development and performance, for example, by influencing its growth, nutrient uptake and protection against pathogens. The next topics will exemplify how the knowledge of microbe–plant interactions can be used to improve crops and to make agricultural practices more environmentally friendly.

4.1. Crop growth and development improvements

Nutrients such as nitrogen and phosphorus are limiting factors for plant growth and development.699 Therefore, inorganic fertilizers are commonly added to soil to enhance crop growth and increase their yields. Despite the fact that this approach is advantageous for agricultural purposes, it involves cost and environmental concerns, such as disturbing the soil's natural chemical composition and plant–microbe interactions.442,700,701 Alternatively, microorganisms that are able to fix nitrogen and/or increase phosphorus availability to plants may be used for biofertilization.538

As mentioned in the previous sections, some plants can establish symbiotic interactions with microorganisms that are able to fix nitrogen, i.e. rhizobia. Many important crops can be cited as being able to establish this symbiosis, such as beans (Phaseolus spp.), peas (Pisum spp.), alfalfa (Medicago spp.), clover (Trifolium spp.), vetch (Vicia spp.), and soybean (Glycine max).442 Therefore, rhizobia–plant symbiosis is explored as an environmentally friendly way to improve crop growth.701 For example, selected rhizobia strains that show good nodulation rates and good nitrogen fixation capacities can be purchased and added to the soil of legume plantations.702,703 However, this practice has shown some constraints such as competition with the indigenous rhizobia present in the soil.702 Knowledge of how the signaling involved in host-specificity works in both partners can be explored to manipulate symbionts genetically to make a desired crop plant that is more able to establish symbiosis with the rhizobia strain of interest, and to control the nodulation process to avoid competition with the potentially less efficient indigenous rhizobial strains present in soil (Fig. 6).362 Research on Nod factors that is aimed at a detailed understanding of the structure–activity relationship can help greatly in manipulating the host range. For instance, introducing a gene that is responsible for O-acetylation of a Nod factor of a European R. leguminosarum strain gave it the ability to colonize and nodulate another host successfully, namely, the Afghanistan pea cultivar.465 It is worth mentioning again that the beginning of the nodulation process triggers the AON (autoregulation of nodulation) pathway, preventing other nodulation events; therefore, understanding the infection pathway deeply is also important for increasing the chances that the desired rhizobia strain will outcompete other strains present in the soil.362,704 For example, a Nod factor regulatory gene was demonstrated to influence the nodulation ability; the nolR mutants of Sinorhizobium medicae WSM419 showed higher nodulation competitiveness over the wild-type in M. truncatula and Medicago sativa.705 Nodulation as well as legume growth and productivity can also be improved by the co-inoculation of rhizobia and PGPR, and this approach is thoroughly reviewed by Mehboob and collaborators.703 This co-inoculation is also described as helping the plant crop to endure abiotic stresses.703 Although it is promising, the approach of inoculating rhizobia into the soil is only valid for plants that can establish rhizobia symbiosis, which is mostly restricted to legume plants.706 Understanding all the processes involved in this symbiotic interaction deeply, including detailed signaling between partners, may allow for the future transposition of this feature to other plants through biological engineering. Despite the complexity and challenges imposed by this approach, AM symbiosis and rhizobia symbiosis share some signaling pathways, such as the Sym pathway, and AM symbiosis is widespread in non-legume plants. Therefore, this evolutionary fact facilitates the bioengineering of non-legumes. Rogers and Oldroyd have nicely reviewed the possible engineering pathways and related challenges involved in this approach to transposing this symbiosis to cereal plants.707

image file: c7cs00343a-f6.tif
Fig. 6 General approaches to plant development improvement and protection against pathogens in agriculture. Metabolites from plants and their associated microorganisms have many favorable aspects, such as their broad biological activities, compatibility with biological systems, and environmental friendliness. Understanding the mechanisms of symbiont host specificity allows for further host manipulation, opening up the possibility of inoculating more efficient symbionts for nutrient uptake, for example. Additionally, microbes known for biosynthesizing growth-promoting compounds as well as microbes known for conferring abiotic stress resistance, as in cases of drought and soil salinity, can also be inoculated into the soil. These approaches help to promote better crop growth and development. The modification of host targets may also be involved in plant defense, such as the JA receptor, which is a recent and promising approach to protect plants. It may be improved because more studies will reveal the signaling pathways whose specific receptors remain unknown. The plant microbiota strategy suggests the use of individual strains or even mixtures of beneficial microorganisms associated with plants, such as endophytes, epiphytes, plant growth promotion rhizobacteria (PGPR) or arbuscular mycorrhizal fungi (AMF). Some genomic approaches can also be used, including the genetic manipulation of plant-colonizing microbiota to improve plant fitness or the direct application of small RNA that targets essential pathogen genes. A combination of strategies that guarantee plant resistance to a variety of pathogens will lower the negative impact on the environment, which is an ideal goal for plant protection over a long-term process.

In addition to biofertilization processes, microbes can promote plant growth through the production of phytohormones and growth regulators, a process known as phytostimulation.37 Endophytes may also positively interfere with some plant processes, such as photosynthesis, improving plant growth.708,709 According to the previously mentioned studies, plant–microorganism signaling enables beneficial microbes to modulate the ET pathway, which is an important resistance mechanism against abiotic stresses. In addition, lowering the plant ET (29, Chart 4) levels is also important for the phytostimulation induced by beneficial microbes.37,340 Therefore, these microbes can also be added to soil to improve crop growth and development (Fig. 6). Beneficial microorganisms, including endophytes, can produce plant hormones such as auxins, cytokinins, abscisic acid, and gibberellin-like substances that may be implicated not only in plant growth promotion but also in disease suppression.508,710–712 Apart from phytohormones, other plant growth-promoting compounds produced by beneficial microorganisms have also been reported, including adenine (157) and adenine ribosides (158, 159) (Chart 4), the polyamine spermidine (110) and spermine (160) (Chart 9) and the VOCs acetoin (33) and 2,3-butanediol (32).340 In addition, 2,3-butanediol (32) as produced by the rhizobacterium Pseudomonas chlororaphis induced drought resistance in Arabidopsis through an SA-dependent mechanism.713 In fact, symbiosis with microorganisms can also be used to adapt crops to dry climates, which is highly important for the future of agriculture due to the global warming threat.714 As mentioned before, associations with mycorrhiza alter the root structure and increase the plant-root area, helping with water uptake in addition to phosphorus uptake. A selected mycorrhizal fungal strain can be inoculated into the soil for plant adaptation during a drought scenario, although with some constraints,715 which can be managed by the co-inoculation of some PGPR that are able to help to control and improve the mycorrhization process, and they are known as the mycorrhization helper bacteria.701,715,716 Armanda and collaborators demonstrated that soil co-inoculation with diverse AMF plus Bacillus thuringiensis increased Lavandula dentata tolerance to drought; an increased biomass was observed, and it reduced the plant oxidative damage of lipids and increased mycorrhizal development under drought conditions.717 Ectomycorrhizal networks are also improved by interacting with PGPR, as reviewed by Rigamonte and collaborators.718 For instance, it was demonstrated that the inoculation of Pseudomonas strains improved L. bicolor (EMF) root colonization in Populus deltoides.719 In addition, endophytic colonization has also been implicated in the amelioration of abiotic stresses. The endophytic fungus P. indica induced drought and salt tolerance in its hosts by increasing antioxidant levels in plants.720,721 Similarly, plants that were colonized by the fungus Trichoderma sp. or the bacterium B. phytofirmans increased their resistance to drought,709,722,723 and fungal endophytes have also been shown to interfere with the cold and chilling tolerance of rice plants.724,725

Diverse co-inoculations of plant symbionts have been described in the literature, and they have revealed how this approach is complex and dependent on the plant and microbial species. Therefore, more studies have focused on understanding plant symbiosis with fungi and bacteria as a community, considering the complex interactions among them. This strategy would permit higher confidence in selecting a microbial consortium that can potentially give the highest plant adaptability to specific environmental conditions, allowing for improved crop growth and yields even under low nutrient/water conditions.714

4.2. Plant protection against pathogens

To continue the current trend in environmentally acceptable agents for protection against pathogens in agriculture, several strategies have been explored (Fig. 6), including the use of natural products. Specifically, the use of intermediates from the tricarboxylic acid cycle (TCA) and fatty acids such as citric (114), succinic (151), α-ketoglutaric (161) (Chart 9), and palmitoleic (162, Chart 6) acids, as well as their derivatives, has been widely studied for plant protection against harmful phytopathogens.726 Additionally, from the wide range of metabolites produced by both sides of plant–fungi interactions, fungal phytotoxins are attractive for herbicidal development as well as natural plant extracts that can be used against plant pathogens in organic agricultural production systems.20 Other approaches include the use of olive mill wastewater as a biopesticide against pathogenic bacteria and fungi due to its phenolic content, primarily 3-hydroxytyrosol (163, Chart 9); as a herbicide against weeds due to its aldehyde and short fatty acid contents; as a disinfectant, as an alternative to sodium hypochlorite; and as a nematicide and insecticide.727

The advantage of using microbial metabolites or analogs of signaling pathways is their compatibility in several biological systems. The induced resistance mediated by natural compounds, such as hexanoic acid (164, Chart 6), polysaccharides (from algae and crustacean exoskeletons) and vitamins [thiamine (165), riboflavin (166), and menadione (167) (Chart 1)], seems to be a reliable method for protecting crops while reducing the amounts of chemical residues in the environment.728 Plant hormones, such as SLs (strigolactones) (Chart 5), also play a role in plant resistance against specific pathogens in addition to acting as regulators of growth and development.393 Interestingly, because SLs promote interactions with symbiotic fungi through the stimulation of hyphal growth and the branching of AMF,729 it was suggested that they could influence the development of pathogenic fungi,393 as mentioned in previous sections. However, there are no consistent data showing alterations in the fungal growth or branching of phytopathogenic fungi.730,731 The regulatory mechanisms of SL-biosynthetic gene expression besides the crosstalk between SLs and other defense-related phytohormones suggest the involvement of SLs in plant biotic stress responses.393 Future research may reveal the molecular mechanisms of these processes and their potential applications in plant protection. Plant treatments with hormone analogs such as methyl salicylate (MeSA, 168), which is synthesized from SA (2) (Chart 4), have demonstrated their potential use in crop protection.732 Additionally, it was demonstrated that abscisic acid (54, Chart 4), but not the SA, JA or ET pathways, played a role in plant resistance against the root phytopathogenic bacteria R. solanacearum in A. thaliana.733

It was recently demonstrated that host target modification could be a promising approach to protect plants from pathogen attack. Because JA (3, Chart 4) plays a central role in plant defense against necrotrophic pathogens, a modification in a JA receptor, or a single amino acid substitution in the JA-Ile-binding pocket of the COI1 protein, was performed, which resulted in the sufficient signal transduction of 3, and fertility and defense against insects, in addition to resistance against P. syringae pathogenic strains.734 That study provided support for the host target modification as a promising approach for plant protection against a wide range of pathogens. Interference with chemical signaling can also be useful. As mentioned previously, the plant hormone IAA (10, Chart 4) also plays a role in plant protection against pathogens, wherein lower 10 concentrations lead to the upregulation of plant defense genes, improving plant resistance to pathogenic attack. Because some pathogens enter plant tissues through stomata and root tips, changes in IAA signaling that affect stomata opening and plant root architecture could restrict pathogen colonization.134 In addition, the ability to control QS (quorum sensing) signals, which are involved in plant–microbe interactions, is also a promising approach for reducing plant disease.735

The effective use of endophytes in plant protection has been delayed due to a poor understanding of the relevance of microbe–plant interactions. Endophytes play roles in plant protection against biotic and abiotic stresses, and they can also harbor viruses as essential partners that contribute to plant heat tolerance, among many other benefits in sustainable agriculture.736,737 Endophytes exhibit specific behavioral traits or features, and their efficient use as biocontrol agents will succeed after the biology behind those specific lifestyles becomes fully understood.738 Among these behavioral traits are the mechanisms of biocontrol through which endophytes may operate (antibiosis, competition, direct parasitism and host-induced resistance).738 These mechanisms can be briefly defined as follows: antibiosis refers to microbial antagonism caused by the action of diffusible substances produced by one organism on another;739–741 competition in this context may correspond to the ability to compete for nutrients for their own benefit;737 direct parasitism is the ability of a pathogen to engage in hyphal attachment and degrade cell walls as mediated by lytic enzymes;742 and host-induced resistance refers to the ability of the microorganism to modulate the plant immune system, as mentioned previously.28 Because many endophytic microorganisms produce a wide range of secondary metabolites with several biological activities,576 it would be ideal to take advantage of the dual roles that several compounds may play, such as antibiotics and elicitors of plant-induced systemic resistance.738 Some secondary metabolites are well-described as important players in endophytic fungus–host plant mutualism. These metabolites include the most commonly detected epichloae alkaloids, such as lolines (e.g., N-methylloline, 169), ergot alkaloids (e.g., ergovaline, 170), lolitrems (e.g., lolitrem B, 171) and peramine (172) (Chart 13). The ergot alkaloids are related to plant defenses against both vertebrate and invertebrate herbivores, whereas the lolitrems act against vertebrates, and lolines and peramine (172) have anti-invertebrate herbivorous activity.514,743 Several studies have demonstrated the increased pathogen resistance of endophyte-infected plants, supporting their potential as efficient biological controls.737,744–746 It has been shown that endophyte colonization triggers the reprogramming of the host metabolism, favoring secondary metabolism and inducing changes in host development.112 One important endophytic functional trait referring to plant protection is the quenching of pathogen QS molecules.185 Endophytes are just part of a complex system, and they are controlled by both the plant host and environmental stimuli.747 Additionally, endophytic bacteria that are in a viable but not cultivable state are also members of the plant microbiome, and therefore they are a hidden reserve for plant protection to be explored.747

image file: c7cs00343a-c13.tif
Chart 13 Epichloae alkaloids and siderophores produced by plant-interacting microbes.

Different members of the plant microbiota can be useful for plant protection. For example, the fungal strain P. indica was able to induce the growth of Chinese cabbage (Brassica campestris subsp. chinensis) and Arabidopsis.748 In fact, P. indica has been considered a representative species among fungi with considerable biological activity and agronomic potential.508Sphingomonas spp. has been reported to inhibit the foliar pathogen P. syringae pv. tomato and suppress disease symptoms in A. thaliana.749Pseudomonas strains protect plants through the production of the antibiotic compound DAPG (5, Chart 1), which may be partially responsible for the control of other soil-borne fungal pathogens present in the disease-suppressive soils.47 Eggplant wilt caused by R. solanacearum was reduced after Solanum melongena L. seeds were inoculated with DAPG-producing endophytic Pseudomonas.750 Another study has shown that a DAPG-producing P. fluorescens strain can co-interact with another PGPR strain (Azospirillum brasilense) on plant roots. DAPG enhanced the ability of A. brasilense to colonize roots and phytostimulate the plant through auxin production.751 Strains of the Gram-positive bacterium B. subtilis have been reported to protect plants against fungal and bacterial pathogens.14Bacillus fortis triggered ISR against Fusarium wilt disease in tomato plants. The compound phenylacetic acid (173, Chart 9) was released from B. fortis and was shown to be the elicitor of defense responses.752 The root-colonizing bacterium B. subtilis produces the VOC acetoin (33, Chart 9), which also triggers the ISR. Through an ET- and SA-dependent and JA-independent response, the plant A. thaliana restricts pathogen dissemination and disease progression in its aerial parts.554 However, another B. subtilis strain confers protection to melon plants against the cucurbit powdery mildew fungus Podosphaera fusca by activating the SA- and JA-dependent defense response.753 Additionally, the cyclic lipopeptide surfactins (e.g., surfactin C15, 174, Chart 12) not only act as antifungal compounds, but they are also a major determinant of ISR activation.753 In addition to surfactins, B. subtilis produces other cyclic lipopeptides such as iturins (e.g., iturin C, 175) and fengycins (fengycin C, 176) (Chart 12) that act as potent antibiotics in the biocontrol of the tomato wilt disease caused by the Gram-negative bacterium R. solanacearum.754 Apart from antibiotic production, siderophore-producing microorganisms compete with phytopathogens for trace metals, and they may also contribute to disease control.538,755 Siderophores such as pyoverdine (177), bacillibactin (178) and desferrioxamines (e.g., desferrioxamine B, 179) (Chart 13), which are produced by Pseudomonas spp., B. subtilis and Streptomyces sp., respectively, have been shown to suppress phytopathogen growth.756–758 In addition to other Pseudomonas MAMPs, 177 can elicit ISR in Arabidopsis plants.759 Interestingly, siderophores have also been reported to play major roles in Epichloë festucae–ryegrass interaction, because the interruption of siderophore biosynthesis disrupts the mutualism between these species.760

The use of the beneficial traits in bacterial species from the genus Paenibacillus demonstrates their increasing role in sustainable agriculture. This genus includes many species that are involved in plant growth promotion, which is related to their biocontrol abilities as inducers of systemic resistance and insecticidal and antimicrobial activities.761 A recent study demonstrated the effectiveness of treating with an epiphytic yeast, Pseudozyma churashimaensis, for the disease suppression of bacterial spots produced by the pathogenic bacterium Xanthomonas axonopodis pv. vesicatoria. In addition, the authors observed the unexpected protection on pepper plants against several viruses, reporting plant protection against bacterial and viral pathogens mediated by a leaf-colonizing yeast for the first time.762 A study with the aim of investigating the contribution of AMF composition in moderating the infection of the crop plant G. max (soybean) by the pathogen P. syringae pv. glycinea (Psg) was performed.763 This study revealed that the mycorrhizal composition was a good predictor of Psg colonization and that AMF has species-specific effects on bioprotection, showing the future potential of AMF for use in organic and sustainable agriculture.763 Another study evaluated the effects of an AMF preparation on bean plants (Phaseolus vulgaris L.) infected with the pathogenic fungus F. solani, which causes Fusarium root rot (FRR) disease.764 That study showed an increase in the bean seedling growth and resistance to F. solani infection as a function of the assemblage of species in the AMF mixture, demonstrating their efficacy in disease biocontrol in bean plants.764 Mixtures of PGPRs were also evaluated for their potential to protect cabbage against black rot disease, and at least one mixture showed consistent biocontrol in the greenhouse and in field tests.765 The way in which microbial consortia can be used as part of a protective approach for plant defense has been reviewed recently.21 Applying microbes as a consortium has great potential in a world in which modern agriculture seeks to minimize its use of chemical fertilizers and pesticides.21 Finally, with the understanding that phytopathogenesis is a consequence of more complex systems than a simple pathogen–host interaction, different aspects of a host-vector microbiome approach for sustainable plant disease management have been reviewed.766 The fundamental basis of this approach lies in the investigation of disease at a community level in which host (plant and insect)–environment–microbiome–pathogen interactions must be simultaneously considered in the way that they may occur naturally.766

Genomic approaches have been applied to ongoing research in the plant disease field. A recent approach was termed host-mediated microbiome selection, or microbiome engineering, and it consists in artificially selecting a host microbiome (based on a host trait, or phenotype, that acts as a selection target) specifically to improve host (plant or animal) performance, which can be applied to agricultural research, for example for improving plant productivity and disease resistance.767 Another innovative approach to plant protection consists in the spraying of double-stranded RNAs (dsRNAs) and small RNAs (sRNAs) that target essential pathogen genes on plant surfaces.768 In targeting fungal ergosterol biosynthesis genes (the same targets of azole fungicide agents) with dsRNA, the necrotrophic fungus Fusarium graminearum was successfully inhibited, supporting the idea that RNA can be used as a treatment to control plant disease.769 As a strategy to slow down the evolution of virulent pathogen genotypes, the combination of common practices for pathogen control together with a disease resistance gene approach has been suggested to guarantee and maximize the durability of the acquired protection.770 With the aim of contributing to the study of pathogen–host interactions in the “post-omics” era, informatics tools have recently become available. The pathogen–host database (PHI-base, enables the discovery of candidate targets in medically and agronomically relevant species, and plant pathogens represent 60% of the species within the PHI-base, providing information about pathogenicity, effector genes and host interactions.771

Together, the ongoing research on well-known plant pathogens will also provide useful information to improve plant fitness, as illustrated by a recent comprehensive review on B. cinerea. These findings show that a combination of “omics” technologies will aid in improving our understanding of the molecular mechanisms underlying plant resistance.772 Recent knowledge of plant–host signaling has enabled researchers to explore novel management approaches by targeting different bacterial signaling processes such as T3SS-secreted compounds, biofilm formation and QS that might be environmentally benign with a low probability of resistance evolution.773 Additionally, genome editing methods, such as TALEN (transcription activator-like effector nucleases)774,775 and CRISPR/CAS9 (clustered regularly interspaced short palindromic repeats),776,777 have been successfully applied to the target genes involved in disease development and for engineering durable plant resistance.773,778 Although these new approaches are still under development, an understanding of chemical signaling between microbes and plants in natural contexts is fundamental and requires further extensive investigation.

5. Conclusions and perspectives

The study of plant–microbe interactions involves several research fields and can be covered from different angles. Great advances in understanding the biology and chemistry of microorganisms and plants have contributed to the understanding of the signaling processes involved in those interactions. The investigation of symbiotic relationships has provided useful information for interpreting the chemical signaling of plant and microbes. The molecular entities involved in signaling on both biological sides, both plants and microbes, must be interconnected with one another to provide functional information about the role of plant–microbe interplay in the consolidation of symbiosis. It is important to note that the functional and trophic classification of microorganisms based on their stage of life is challenging and difficult to use to understand their specific roles in natural environments. Moreover, according to several examples mentioned in this review, the particularity of every biological system must be studied in detail because the role that one molecule plays in one system at a specific time point may differ in another system. For example, some microorganisms may be endophytes in one plant but turn pathogenic in another; some molecules may trigger the immune system in one plant but not in another one due to differences in or a lack of specific receptors. Additionally, even though an important body of knowledge has been built over the last few decades about plant–microbe symbiosis, it is based mostly on axenic conditions, or in a dual interaction with a plant host. This type of approach is important to start understanding complex systems, but it does not necessarily reflect what is occurring in the real environment. Therefore, a step ahead should be made towards understanding a more complex scenario. Recent developments with the purpose of obtaining in situ information will allow researchers to confirm the specificity of the signaling processes in different biological systems and understand symbionts as a consortium. For example, the ability to monitor root–bacteria interactions at a spatiotemporal resolution was successfully accomplished by using a creative device called the TRIS (tracking root interaction system).779 The TRIS device enabled researchers to investigate fundamental questions about root–bacteria interactions as follows: the initiation of the bacterial colonization of the root surface, including competition between different bacterial species, the ability of bacteria to distinguish among plant root genotypes, and the confirmation of a hypothesis of bacterial accumulation via chemotaxis towards exudates secreted from the root surface.779 This remarkable study opens the door for potential applications, including studies of microbial dynamics in pathogenic processes or during the establishment of plant–microbe interactions other than model systems. Complementary approaches include the mapping of molecular entities, for instance in the rhizosphere, via mass spectrometry imaging.780 Those approaches, combined with in vitro and in field experiments, structure–activity relationship studies, and the continuous development of analytic and bioinformatic tools, will facilitate the integration of the relevant information to understand signaling processes completely in plant–microbe interactions. This integration will not only aggregate valuable knowledge and shed light on how complex interactions occur in nature, but it will also benefit agriculture. A more accurate description of plant–microbe interactions can guide biotechnological approaches to providing products and solutions for problems in modern agriculture, for example by using a specific and controlled microbial consortium for each type of soil and climate with the aim of increasing crop productivity. Human health can also benefit from these approaches once several important plant-derived therapeutic drugs have been identified in plant-associated microorganisms. Understanding the complex chemical signaling in these intimate symbioses might contribute to the design of new approaches that employ endophytic microorganisms in the biotechnological production of drugs.

Here, we have reviewed plant–microbe interactions that primarily involve bacteria and fungi. However, other key players such as virus and nematodes and even insects and other herbivores must be considered to elucidate the complete chemical communication and elicitation that occur in plants. Finally, we have shown how chemical signaling and microbe–plant interactions can be beneficial for agricultural purposes, although those applications will require further in field studies to demonstrate their efficacy and safety.

Conflicts of interest

There are no conflicts of interest to declare.


This work was partially supported by São Paulo Research Foundation (FAPESP) grants #2013/50954-0 (FAPESP/FIC-NIH), 2013/07600-3 (CEPID-CIBFar), and 2008/09540-0 (Regular Research Grant). FOC acknowledges the National Council for Scientific and Technological Development (CNPq) for fellowship #150572/2015-8. AMCR and RCP acknowledge FAPESP for fellowships #2012/21803-1 and #2011/12910-6, respectively. MTP also acknowledges the CNPq for grant #307147/2014-2. The authors also acknowledge the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) for supporting this research.


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Denotes equal contribution.
Current address: Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (IPPN-UFRJ), Brazil.

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