Stress-related and spontaneous stage differentiation of Toxoplasma gondii

Abstract

Toxoplasma gondii is an obligatory intracellular parasitic protozoan that infects a variety of avian and mammalian hosts including up to one third of the human population worldwide. Developmental differentiation between distinct stages, i.e. sporozoites, tachyzoites and bradyzoites is fundamental for the parasite life cycle and for transmission between hosts. It is also interconnected with the pathogenesis of overt toxoplasmosis and makes T. gondii an important opportunistic pathogen of humans. In order to delineate the underlying mechanisms, several cell culture differentiation systems have been developed which mimic the transition from fast-replicating tachyzoites to slowly proliferating bradyzoites in vitro. Since exogenous stress factors, i.e. alkaline pH, IFN-γ and other proinflammatory cytokines, chemicals or drugs, heat shock, and deprivation of nutrients have been shown to increase the efficacy of bradyzoite development in vitro, Toxoplasma stage differentiation is largely viewed as a stress-related response to hostile environmental conditions. However, tachyzoite to bradyzoite differentiation also occurs spontaneously in vitro and this raises questions about the importance of stress conditions for triggering stage conversion. High frequencies of spontaneous bradyzoite development in primary and permanent skeletal muscle cells, i.e. cells that preferentially harbour bradyzoite-containing tissue cysts in vivo suggest that the host cell type may be critical. Furthermore, the host cell transcriptome, including the expression of distinct host cell genes, has recently been shown to trigger bradyzoite development and cyst formation. Together, these results strongly indicate that the complex cellular environment, besides exogenous stress factors, may govern the developmental differentiation of T. gondii.