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Are Heat Shock Protein 90 (Hsp90) Co-Chaperones Virulence Factors in the Human Fungal Pathogen Candida albicans?

Periodic Report Summary 1 - HSP90COCHAPERONES (Are Heat Shock Protein 90 (Hsp90) Co-Chaperones Virulence Factors in the Human Fungal Pathogen Candida albicans?)

Each year 700 people die in the UK of candidemia, a systemic blood stream infection caused by the fungus Candida albicans. In healthy people C. albicans resides in the oral cavity and the gastrointestinal tract without causing any symptoms. Upon changes in an individual’s immune status, however, C. albicans can cause life-threatening infections that are associated with mortality rates of ~50%. These unacceptably high mortality rates are due to a lack of suitable antifungal drug targets and efficient therapies.
Efforts aiming to identify new drug targets, demonstrated that the environmentally responsive chaperone heat shock protein 90 (Hsp90), which is a central regulator of the cell’s protein balance, regulates C. albicans virulence and stress response pathways. While this sounds promising, Hsp90 efficacy is hampered by its highly conserved nature. Inhibiting Hsp90 in mice suffering from candidemia in combination with currently available antifungal drugs resulted in severe host toxicity. To mitigate this problem and to further develop chaperones as antifungal drug targets, this proposal aims to characterize Hsp90’s much-less conserved and understood co-chaperones, which regulate Hsp90 function and activity. Interestingly, most Hsp90 co-chaperones in C. albicans are located near the chromosome ends, which is reminiscent of other genes regulating virulence and stress responses, such as Candida’s TLO genes. Hence, this project specifically focuses on (1) understanding the co-chaperones’ role in fungal virulence, (2) determining if and how their near telomeric locations affects their regulation, (3) identifying the factors that regulate their expression.
Two graduate students, now in their 2nd and 3rd year, contribute to this project. The 3rd year student, investigating the role of Hsp90 co-chaperones in virulence, selected five co-chaperones that are not essential for growth, to not elicit selective pressure for drug resistance, and examined their contributions to growth in in vivo and in vitro virulence assays. Indeed, certain co-chaperones are important for survival of oxidative stress and heat shock, for biofilm formation, and the survival of an invertebrate model of fungal virulence. The 2nd year student, who examines variations in co-chaperone expression, discovered an intriguing pattern of co-regulation. When measuring protein levels in virulence-related conditions such as filamentous growth and biofilm formation, the student noticed that Hsp90-activating and inhibiting co-chaperones were co-regulated.
Our results allows us to determine which co-chaperones are important for virulence and thus long-term development as drug targets and which co-chaperones Thus, towards fulfilling grant objectives (1) and (3). Objective (2) is currently under investigation but has not yielded any results yet.
Receiving this grant has had a positive career impact. The fellow transitioned to probationary lecturer in March 2015 and has since passed the 1st year probationary review (February 2016) successfully. The fellow is furthermore actively participating in departmental life and organization by contributing to several committees involved in teaching and research. This project will yield up to three publications, which will be important for the fellow’s passing of probation and promotion to senior lecturer.