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 causes 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, which is a trait critical for virulence, or the ability to cause disease. The capacity to thrive at human body temperature is a pre-requisite for a human pathogen, and temperature is a central cue governing fungal drug resistance, morphogenesis, and virulence. This research focuses on the central regulator of the heat shock response, Hsf1, which regulates expression of ~3% of the genome in response to elevated temperature. We recently discovered that Hsf1 regulates drug resistance and morphogenesis of the leading fungal pathogen of humans, Candida albicans. Here, we will investigate the mechanisms through which Hsf1 regulates drug resistance, morphogenesis, and virulence. Further, we will evaluate the potential of targeting the heat shock response in the treatment of life-threatening fungal infectious disease. Targeting the human Hsf1 counterpart provides a promising therapeutic strategy for neurodegenerative diseases and cancer, and modulation of fungal Hsf1 may also hold great therapeutic potential. Elucidating the circuitry through which Hsf1 regulates drug resistance, morphogenesis, and virulence is poised to both reveal new insights into the fundamental biology underpinning temperature sensing and establish novel and much-needed strategies to save human lives.