Mechanisms of Host Adaptation for Candida albicans

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DESCRIPTION (provided by applicant): The obligate commensal organism Candida albicans colonizes the intestinal tract of its human host, and normally causes no disease. However, immunocompromised individuals risk acquiring opportunistic infections originating from this commensal population of microflora. Thus, a clear understanding of the transition from commensal to pathogen is a public health imperative. In fungal pathogens such as Cryptococcus neoformans and Aspergillus fumigatus, the membrane-bound sterol regulatory element binding protein (SREBP) is a key hypoxic transcription factor required for host adaptation and virulence. In mammalian cells, SREBPs regulate lipid homeostasis. C. albicans has an SREBP homolog called Cph2, but known SREBP functions such as virulence, the hypoxic response, and regulation of sterol homeostasis do not require CPH2. However, C. albicans host intestinal colonization requires Cph2, suggesting that Cph2 controls an undefined transcriptional program essential for commensalism. In mammalian cells and the basidiomycete C. neoformans, SREBP proteolysis requires the Golgi Site-1 and Site-2 proteases. However, ascomycetous fungi like C. albicans lack the Site-2 protease. Our recent work in Schizosaccharomyces pombe identified a Golgi E3 ligase complex required for SREBP activation. C. albicans contains homologs of all subunits in this Defective for SREBP Cleavage (Dsc) E3 ligase complex. Here, we bring our studies of SREBP and the Dsc E3 ligase complex to C. albicans. Because the qualities of the host environment that generate a niche for this obligate commensal are unknown, we will focus on C. albicans host intestinal colonization. Knowing specific requirements for colonization will allow comparison between the commensal and the pathogenic environments, elucidating potential targets for therapeutics and treatment of C. albicans infections. We hypothesize that the C. albicans SREBP Cph2 is a principal transcription factor required for gene expression during host intestinal colonization and that the conserved Dsc E3 ligase complex functions in intestinal colonization by mediating Cph2 activation. Our specific aims are: AIM 1. To determine the transcriptional targets of Cph2 during intestinal colonization. AIM 2. To test whether Cph2 function in intestinal colonization requires cleavage and DNA binding. Identification of Cph2 transcriptional targets in the host intestine represents the first step toward understanding the host environment that Candida albicans inhabits. Our studies will yield protocols for the identification of fungal gene expression programs in the mouse intestine, providing a blueprint for studies of other transcriptional networks.