TY - JOUR
T1 - Changes in mammalian copper homeostasis during microbial infection
AU - Culbertson, Edward M.
AU - Khan, Aslam A.
AU - Muchenditsi, Abigael
AU - Lutsenko, Svetlana
AU - Sullivan, David J.
AU - Petris, Michael J.
AU - Cormack, Brendan P.
AU - Culotta, Valeria C.
N1 - Funding Information:
We would like to thank Angelique Besold, Kimberly Jasmer, and Adriano Casin for technical assistance with mouse work. This research was supported by NIH grants RO1 AI119949 and RO1 GM50016 (VCC), RO1 AI046223 (BPC), RO1 DK117396 (SL), RO1 CA190265 (MJP), RO1 AI111962 (DJS) and F31 DK111114 (EMC), and the Johns Hopkins Malaria Research Institute and the Bloomberg Family Foundation.
Publisher Copyright:
© 2020 The Royal Society of Chemistry.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
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U2 - 10.1039/c9mt00294d
DO - 10.1039/c9mt00294d
M3 - Article
C2 - 31976503
AN - SCOPUS:85082384363
VL - 12
SP - 416
EP - 426
JO - Metallomics
JF - Metallomics
SN - 1756-5901
IS - 3
ER -