Grant: Project Grant

The impact of fungal pathogens on human health is devastating. They infect billions of people around the globe, and kill more than 1.5 million each year. The most vulnerable are people with reduced immune function, such as those with HIV or those undergoing immune suppressing treatments for cancer or organ transplants. One of the leading fungal pathogens of humans is Candida albicans. It kills ~40% of people suffering from bloodstream infections. Treating these infections is extremely difficult, as fungi are closely related to humans and there are very few drugs that kill the fungus but not the host. With the emergence of drug resistance, it is now critical to develop new therapeutic strategies. To address this important clinical need, it is critical to uncover the genes and genetic networks that are required for the pathogen to survive, evolve resistance to antifungal drugs, and cause disease. We discovered a central regulator that is essential for survival of fungal pathogens, and required for drug resistance and virulence. This regulator is a transcription factor called Hsf1 that controls the expression of hundreds of genes in the genome, including genes that are required for adapting to temperature stress. The capacity to respond to elevated temperature is required for a pathogen to survive in the human host, with elevated temperature in the form of fever as a ubiquitous host response to defend against infection. Our proposed studies will leverage state-of-the-art analyses to define the complete set of genes that Hsf1 controls, and to identify the genes through which it regulates drug resistance and virulence. Ultimately, we will assess the therapeutic potential of targeting Hsf1-dependent circuitry in diverse fungal pathogens and models of disease. This research will reveal new approaches to cripple fungal pathogens, and enable development of novel therapeutic strategies to improve clinical outcome for millions of people.