Copper is a highly reactive element and based on its potential toxicity, animals use the deleterious properties of Cu in anti-microbial weaponry during infectious disease. Both bacterial and fungal pathogens are attacked with toxic doses of Cu inside the animal host. However, Cu is also an essential nutrient that microbes must acquire from the host. Currently, little is understood regarding host-pathogen competitions for Cu as a nutrient. To shed light into the biology of Cu during infectious disease, this research proposal focuses on Candida albicans, the most prevalent of human fungal pathogens. C. albicans requires Cu to maintain activity of a family of extracellular superoxide dismutase (SOD) enzymes that protect the yeast from the host oxidative burst and are important for virulence. Our findings show these Cu-SODs are unprecedented in structure and function in that they lack a Zn co-factor and contain a highly irregular open Cu site that may easily capture Cu from the host. We find the intracellular Cu-SOD of C. albicans is also remarkable in that this enzyme is replaced with a non-Cu alternative (Mn-SOD3) when the yeast is starved for Cu. This swapping of SOD enzymes is part of a large adaptation to Cu starvation, and surprisingly this Cu stress response becomes evident during C. albicans invasion of the kidney in vivo. To our knowledge this is the first documented evidence for host limitation of Cu during infection. We hypothesize that the host not only attacks pathogens with elevated Cu, but can also withhold this nutrient from invading microbes and C. albicans can adapt to both. Here we shall use the family of Cu SODs in C. albicans as a read-out for fungal Cu utilization during two extremes of host Cu availability, namely the high Cu of macrophages and the low Cu of kidney infection. The extracellular Cu-SODs become particularly important during fungal encounters with the oxidative burst of macrophages and we propose that C. albicans efficiently utilizes macrophage Cu to charge its SODs for an anti-oxidant defense.
In Aim 1 (To define the metal binding properties and function of diverse SOD5-like proteins in C. albicans) we address the Cu binding capacities of the extracellular SODs as predictive indicators of how well these enzymes can maintain activity at the host-pathogen interface. Additionally we will explore the function of an unknown member of the extracellular SOD family, namely SOD6, as a potentially new Cu- requiring entity for fungal pathogenesis.
In Aim 2 (To understand C. albicans utilization of host copper as a nutrient during macrophage infection), we examine activation of the extracellular fungal SODs in a macrophage infection model and define the pathway by which macrophage Cu is ultimately delivered to the active site of the fungal SOD enzymes. Lastly, Aim 3 (To understand the fungal Cu starvation response at the host-pathogen interface) will explore the kidney model of infection and define the mechanism whereby the host withholds Cu from C. albicans as the first documented nutritional immunity response involving Cu. Collectively, these studies promise to provide new insight into the implications for Cu as a nutrient for fungal pathogenesis.

Public Health Relevance

Candida albicans is the most prevalent of human fungal pathogens and remains an important concern in public health. To survive in a human host, C. albicans must acquire sufficient levels of Cu as a nutrient to maintain activity of its anti-oxidan enzymes, the superoxide dismutases (SOD). This research will explore ways the pathogen use host Cu as a nutrient for its SODs and anti-oxidant defense during infectious disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Love, Dona
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Johns Hopkins University
Schools of Public Health
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Robinett, Natalie G; Peterson, Ryan L; Culotta, Valeria C (2018) Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains. J Biol Chem 293:4636-4643
Liu, Ning-Ning; Uppuluri, Priya; Broggi, Achille et al. (2018) Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog 14:e1007076
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Besold, Angelique N; Gilston, Benjamin A; Radin, Jana N et al. (2017) The role of calprotectin in withholding zinc and copper from Candida albicans. Infect Immun :
Broxton, Chynna N; Culotta, Valeria C (2016) An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase. PLoS One 11:e0168400
Broxton, Chynna N; Culotta, Valeria C (2016) SOD Enzymes and Microbial Pathogens: Surviving the Oxidative Storm of Infection. PLoS Pathog 12:e1005295
Besold, Angelique N; Culbertson, Edward M; Culotta, Valeria C (2016) The Yin and Yang of copper during infection. J Biol Inorg Chem 21:137-44

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