Grant: Operating Grant

Cancer patients and other individuals with reduced immune function, such as those with HIV or undergoing surgery or organ transplantation, are vulnerable to life-threatening fungal infections. Candida species are the most prevalent cause of fungal infection, with mortality rates approaching 50%. Fungal infections are notoriously difficult to treat, in part because fungi are closely related to humans and it is challenging to identify drugs that kill the pathogen but not the host. The efficacy of antifungal drugs is compromised by the emergence of drug resistance. This research is focused on dissecting the molecular mechanisms by which fungi acquire drug resistance and regulate morphogenesis, a trait critical for virulence, or the ability to cause disease. We discovered that the molecular chaperone Hsp90 is a key regulator of fungal drug resistance, morphogenesis and virulence. Hsp90 helps hundreds of proteins in the cell fold and function. When Hsp90 function is compromised, proteins misfold and cellular signaling goes awry. Here, we will provide the first global analysis of all the proteins that Hsp90 interacts with in the leading human fungal pathogen, Candida albicans. We will discover novel regulators of Hsp90 function and new targets through which Hsp90 governs drug resistance, morphogenesis, and virulence. We will also evaluate the potential of targeting the Hsp90 chaperone network in the treatment of life-threatening fungal infections. Targeting the human Hsp90 counterpart provides a promising therapeutic strategy for cancer, neurodegenerative disorders, and inflammatory diseases, and modulating fungal Hsp90 holds great potential for treating infectious disease. Elucidating the circuitry through which Hsp90 regulates drug resistance, morphogenesis, and virulence is poised to both reveal new insights into the fundamental biology underpinning protein homeostasis and cellular signaling, and establish novel and much-needed strategies to save human lives.