CANDIDA ALBICANS SUPEROXIDE DISMUTASE AS PART OF AN ADAPTIVE RESPONSE TO COPPER DURING INFECTION
Li, Cissy X
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Candida albicans is a human fungal pathogen of important public health relevance. Virulence of C. albicans requires members of a family of antioxidant enzymes called superoxide dismutases (SODs). C. albicans has an unusually large collection of SODs that includes a rare pairing of a Cu/Zn-Sod1 and a Mn-Sod3 in the cytosol. The biology and regulation of these two SODs was poorly understood, and was the subject of investigation in this thesis. First, we found that C. albicans Sod1 is relatively unstable compared to homologs in various other organisms (Chapter 2). We also uncovered evidence suggesting that the physical interaction between C. albicans Sod1 and its copper chaperone Ccs1 is unusually species-specific. These traits may reflect this yeast’s adaptation to life as a pathogen. Although others have shown that Cu/Zn-Sod1 and Mn-Sod3 were alternatively expressed at the mRNA level, nothing was known about the regulation and rationale of these seemingly redundant enzymes. We establish that these two SODs are modulated to adapt to fluctuations in copper bioavailability (Chapter 3). Utilizing both a copper-dependent and a copper-independent SOD ensures that C. albicans can maintain constant SOD antioxidant activity regardless of the surrounding copper environment. This alternative regulation of Cu/Zn-Sod1 and Mn-Sod3 employs the copper-sensing transcription factor Mac1, using a novel mechanism. We discovered that the host response to fungal infection includes fluctuation of kidney copper. Meanwhile, C. albicans expertly switches its cytosolic SODs to adapt to these changes in copper. This is the first evidence for possible copper utilization in host nutritional immunity. Besides copper, other kidney biometals are also affected by C. albicans infection (Appendix I). Strikingly, sites of calcium deposits and zinc depletion overlap with immune infiltration at fungal lesions. Finally, phagocytes are known to utilize copper toxicity to kill pathogens. We use a fluorescent probe to directly measure for the first time intracellular copper of C. albicans during the macrophage copper burst (Appendix II). Altogether, this work illustrates the importance of metals at the host-pathogen interface. Specifically, we explore the host utilization of copper for microbial defense, and the adaptive capabilities of C. albicans using two different SODs.