In the HIV- positive population, the second most frequent cause of vaginal and esophageal candidiasis is Candida glabrata. This is in part due to the relative resistance of C. glabrata to azole therapeutics. C. glabrata is also prevalent in ICUs. The interaction of C. glabrata with the host is not well understood. The objective of this proposal is to analyze the molecular interactions of C. glabrata with its host and to identify virulence factors in C. glabrata. Molecular and genetic manipulation is possible in C. glabrata, and is made easier by the fact that C. glabrata is haploid. The investigator has generated random insertion mutants and developed a strategy to screen up to 96 mutants in parallel in a single pool. Using this strategy, he has identified the EPA1 gene, an adhesin mediating binding to carbohydrates on the cell surface of the host. In this proposal, he will characterize this adhesin's ligand specificity, domain structure and sub-cellular localization. Genetic and molecular approaches will be used to identify other adhesins, with the eventual aim to characterize the majority of C. glabrata adhesins relevant to the host-cell interaction. The genetic tools developed in the analysis of EPA1 allow for a broad genetic analysis of virulence. The investigator will screen directly for avirulent mutants in murine models of mucosal and systemic candidiasis. A number of secondary screens will identify those mutants involved in discrete interactions with specific host molecules.
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