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Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5336-42. doi: 10.1073/pnas.1513447112. Epub 2015 Sep 8.

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase.

Author information

1
Department of Biochemistry and Molecular Biology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205;
2
Department of Pathology and Division of Microbiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
3
Department Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201;
4
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Department of Biochemistry and Molecular Biology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205; vculott1@jhu.edu.

Abstract

Copper is both an essential nutrient and potentially toxic metal, and during infection the host can exploit Cu in the control of pathogen growth. Here we describe a clever adaptation to Cu taken by the human fungal pathogen Candida albicans. In laboratory cultures with abundant Cu, C. albicans expresses a Cu-requiring form of superoxide dismutase (Sod1) in the cytosol; but when Cu levels decline, cells switch to an alternative Mn-requiring Sod3. This toggling between Cu- and Mn-SODs is controlled by the Cu-sensing regulator Mac1 and ensures that C. albicans maintains constant SOD activity for cytosolic antioxidant protection despite fluctuating Cu. This response to Cu is initiated during C. albicans invasion of the host where the yeast is exposed to wide variations in Cu. In a murine model of disseminated candidiasis, serum Cu was seen to progressively rise over the course of infection, but this heightened Cu response was not mirrored in host tissue. The kidney that serves as the major site of fungal infection showed an initial rise in Cu, followed by a decline in the metal. C. albicans adjusted its cytosolic SODs accordingly and expressed Cu-Sod1 at early stages of infection, followed by induction of Mn-Sod3 and increases in expression of CTR1 for Cu uptake. Together, these studies demonstrate that fungal infection triggers marked fluctuations in host Cu and C. albicans readily adapts by modulating Cu uptake and by exchanging metal cofactors for antioxidant SODs.

KEYWORDS:

copper; fungal infection; superoxide dismutase

PMID:
26351691
PMCID:
PMC4586888
DOI:
10.1073/pnas.1513447112
[Indexed for MEDLINE]
Free PMC Article

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