Does developmental regulation of heat shock protein 90 co-chaperones affect virulence in Candida albicans?

Abstract

The fungal-pathogen Candida albicans causes invasive systemic infections and life-threatening biofilms associated with increasing mortality rates. Due to rapid emergence of resistance to anti-fungal drugs, in combination with a paucity of effective drug targets, treatment options for Candida-related infections are alarmingly inadequate. Heat shock protein 90 (Hsp90), a highly conserved regulator of virulence, morphogenesis, biofilm development, and drug resistance, holds potential as an indirect therapeutic target to enhance antifungal drug efficacy. Hsp90 is modulated via a network of less conserved cochaperones, which could provide potential targets for drug development if implicated in C. albicans virulence.
When measuring expression of Hsp90 and five cochaperones at the transcriptional and post-transcriptional levels, Hsp90 and Sti1-TAP were differentially expressed between biofilm and planktonic filamentous conditions. Significant SBA1 upregulation was observed in biofilm, but not planktonic filamentous conditions which suggested involvement in either maintenance of mature biofilms or stress responses. Microscopy showed filamentation was not dependent on expression of Aha1, Sba1, or Sti1. Comparative analyses revealed TPR-containing cochaperones CPR6, CNS1, and CPR7 are differentially coregulated under various hyphal-inducing conditions. Furthermore, Hsp90 cochaperones exhibited differential regulation with regard to environmental stimuli, even in yeast-locked morphological forms. When larval models M. sexta and G. mellonella were challenged with cochaperone deletion mutants, no difference in mortality compared to wild-type-challenged larvae was observed.
Thus, these studies present first evidence that C. albicans Hsp90 cochaperone transcriptional regulation is independent of morphogenesis but governed by environmental stimuli. Although Hsp90 modulates virulence and morphogenesis in C. albicans, Hsp90 cochaperones are not implicated in these processes. These findings reveal the transcriptional and post-transcriptional landscape of Hsp90 cochaperones under two virulence-associated conditions, report filamentation phenotypes of cochaperone deletion mutants, elucidate the impact of Hsp90 cochaperones on fungal virulence, and contribute to the promising development of Hsp90-inhibiting antifungal drug therapies to treat Candida-related infections.

Date of Award	1 Nov 2021
Original language	English
Awarding Institution	University of Bath
Supervisor	Andrew Preston (Supervisor) & Jean Van Den Elsen (Supervisor)