Adaptation of Candida albicans to Reactive Sulfur Species
Doctor of Philosophy
The opportunistic fungal pathogen Candida albicans is both a common commensal of the human microbiota and an agent of fatal systemic infections. C. albicans inhabits the mouth and skin, as well as gastrointestinal and genitourinary tracts of humans. One attribute that allows C. albicans to inhabit such physiologically distinct niches is the ability to resist and adapt to various oxidative stresses. This includes stress caused by reactive sulfur species (RSS), such as sulfite, produced by C. albicans, sulfate-reducing commensal microbes, and the host immune system. From a collection of transcription factor deletion mutants, only the mutant lacking the zinc cluster factor gene ZCF2 was found to be specifically sensitive to sulfite. In my thesis I show that C. albicans distinctively adapts to sulfite stress, and that Zcf2, as well as the sulfite exporter, Ssu1, are required for that response. Gene expression profiling revealed that Zcf2 is required for the induction of genes predicted to remove sulfite from cells, and increase the import of a subset of nitrogen metabolites. Additionally, analysis of mutants in the sulfate assimilation pathway show that sulfite conversion to sulfide accounts for part of sulfite toxicity and that Zcf2-dependent expression of SSU1 is induced by both sulfite and sulfide. Mutations in the SSU1 promoter that selectively inhibit induction by sulfite, or the reactive nitrogen species (RNS), nitrite, a previously reported activator of SSU1, lead to the identification of distinct cis-acting regions in the SSU1 promoter. This supports a model in which RNS and RSS-induction of SSU1 are mediated by parallel pathways. Lastly, I found that endogenous sulfite production leads to an increase in resistance to exogenously added sulfite. Taken together, these data demonstrate that C. albicans has a unique response to sulfite that differs from the general oxidative stress response, and that adaptation to internal and external sulfite is largely mediated by one transcription factor and one effector gene.
Candida albicans; Zcf2; Sulfite; Sulfide