Candida albicans is a leading human fungal pathogen that causes life-threatening 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 target for antifungal therapeutics and illuminate the mechanisms by which one of the most ancient and conserved cellular regulators governs fungal biology and disease.
My first goal is to map the physical and genetic interactors of Hsp90 in Candida albicans using proteomic and chemical genomic approaches. The second goal is to determine the biological role of these Hsp90-dependent proteins on the virulence-related phenotypes of drug resistance, morphogenesis, and stress response. Selected candidate proteins will be tested in invertebrate models of virulence.
