A Genetic Approach to Virulence in C. albicans

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DESCRIPTION (provided by applicant): Candida albicans is the most common fungal pathogen worldwide and yet there is limited understanding of its virulence mechanisms, particularly in comparison to those of bacterial pathogens. This poverty of understanding on the academic front is associated with a dearth of safe, effective clinical diagnostic and therapeutic tools. Forward genetic screens such as signature tagged mutagenesis have been fundamental in identifying the major virulence pathways in bacteria. Such screens have not been performed in C. albicans, however, because of experimental limitations imposed by a diploid genome and the absence of a complete mating cycle. I have recently developed methods and reagents that mitigate these obstacles. The goal of this proposal is to perform the first large-scale genetic analysis of virulence in C. albicans in order to identify and study the key determinants of pathogenesis in this organism. To accomplish these goals, I have the following specific aims: (1) Construct a signature-tagged knockout library of C. albicans homozygous disruption mutants; (2) Perform a genetic screen for virulence mutants in a murine infection model of disseminated Candidiasis; (3) Characterize the virulence defects of the mutants through secondary screens of specific steps in the pathogenesis cycle; and (4) Carry out detailed cell biological, molecular biological, and biochemical analysis of selected mutants of special interest. Results from this work should enhance our understanding of fungal pathogenesis and identify novel targets for antifungal therapy.