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Changes in mammalian copper homeostasis during microbial infection

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Abstract

Animals carefully control homeostasis of Cu, a metal that is both potentially toxic and an essential nutrient. During infection, various shifts in Cu homeostasis can ensue. In mice infected with Candida albicans, serum Cu progressively rises and at late stages of infection, liver Cu rises, while kidney Cu declines. The basis for these changes in Cu homeostasis was poorly understood. We report here that the progressive rise in serum Cu is attributable to liver production of the multicopper oxidase ceruloplasmin (Cp). Through studies using Cp−/− mice, we find this elevated Cp helps recover serum Fe levels at late stages of infection, consistent with a role for Cp in loading transferrin with Fe. Cp also accounts for the elevation in liver Cu seen during infection, but not for the fluctuations in kidney Cu. The Cu exporting ATPase ATP7B is one candidate for kidney Cu control, but we find no change in the pattern of kidney Cu loss during infection of Atp7b−/− mice, implying alternative mechanisms. To test whether fungal infiltration of kidney tissue was required for kidney Cu loss, we explored other paradigms of infection. Infection with the intravascular malaria parasite Plasmodium berghei caused a rise in serum Cu and decrease in kidney Cu similar to that seen with C. albicans. Thus, dynamics in kidney Cu homeostasis appear to be a common feature among vastly different infection paradigms. The implications for such Cu homeostasis control in immunity are discussed.

Graphical abstract: Changes in mammalian copper homeostasis during microbial infection

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Article information


Submitted
03 Dec 2019
Accepted
17 Jan 2020
First published
17 Jan 2020

Metallomics, 2020, Advance Article
Article type
Paper

Changes in mammalian copper homeostasis during microbial infection

E. M. Culbertson, A. A. Khan, A. Muchenditsi, S. Lutsenko, D. J. Sullivan, M. J. Petris, B. P. Cormack and V. C. Culotta, Metallomics, 2020, Advance Article , DOI: 10.1039/C9MT00294D

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