Candida albicans is one of the top five most common causes of nosocomial bloodstream infections, and systemic infections are fatal in 40% of cases in the UK. Treatment of candidiasis presents a challenge owing to a lack of efficacious drugs and a paucity of suitable drug targets for development. Novel drug targets are urgently needed in order to tackle this growing public health problem. Hsp90 is an important regulator of C. albicans virulence, but is highly conserved with the human orthologue, making it a poor drug target. Hsp90 functions in concert with associated co-chaperones, which are less conserved. The sub-telomeric location of co-chaperone genes is reminiscent of virulence gene families, including the TLO genes in Candida. The principle aim of this study was to elucidate the roles of five Hsp90 co-chaperones in C. albicans virulence; Ssa1, Ssa2, Sba1, Aha1, and Sti1. All five were found to be instrumental in biofilm formation and in killing of an invertebrate host model, Manduca sexta fifth instar larvae. Ssa1, Sba1, and Sti1 were identified as regulators of fluconazole resistance. Ssa2 was broadly found to be a repressor of virulence traits, though apparently with an overall fitness benefit to the cells in the host. The secondary aim was to investigate the silencing effects of histone deacetylases on Hsp90 co-chaperone gene expression. Hst1 was found to reduce silencing, while Hst2 was found to increase silencing of Hsp90 co-chaperones by heterochromatin formation.This study enhances understanding of diverse C. albicans virulence traits and how the dynamic Hsp90 co-chaperone complex regulates them, as well as how genomic locale implicates genes in virulence functions. This may inform future development of novel antifungal drugs.
|Date of Award
|18 Jun 2018
|Stephanie Diezmann (Supervisor) & Laurence Hurst (Supervisor)