Candida albicans is a leading human fungal pathogen that causes lifethreatening systemic infections, especially in immunocompromised individuals. Targeting the Hsp90 chaperone protein provides a powerful therapeutic strategy for fungal disease. However, clinical utility depends upon identifying components of the Hsp90 network that can be selectively targeted in the pathogen without harming the infected host. A combination of proteomic and chemical genomic approaches will provide the first global analysis of the Hsp90 chaperone network in C. albicans. This will test the hypothesis that Hsp90 and its co-chaperones interact with different client proteins under specific environmental conditions, enabling a range of adaptive responses that allow for virulence. Since Hsp90 is a central hub for protein homeostasis, the proposed research will identify Hsp90 interactors with important roles in stress response, drug resistance, morphogenesis, and virulence. These interactors will be prioritized based on: 1) identification in multiple screens; 2) magnitude and reproducibility of the genetic interaction or mutant phenotype; and 3) novelty of the interaction. All physical interactions will be validated by reciprocal co-immunoprecipitation, and all genetic interactions or morphogenetic defects will be validated by complementation with the wild-type allele. Epistasis analysis will determine the structure of the Hsp90 genetic network. Finally, the candidate targets will be evaluated for their role in virulence. This work will reveal novel targets for antifungal therapeutics and illuminate the mechanisms by which one of the most ancient and conserved cellular regulators governs fungal biology and disease.
Due to the rise in the prevalence of immunocompromised and hospitalized patients, there is an increasing population of individuals that are highly susceptible to invasive infections by fungal pathogens. The major cause of nosocomial fungal infections is Candida albicans, and Hsp90-mediated processes are vital in allowing C. albicans to cause disease. By identifying Hsp90 interacting proteins in C. albicans, we will determine mechanisms for C. albicans pathogenesis and define a novel set of potential drug targets.
