Grant: Project Grant

Fungal infections are an underappreciated and growing threat to human health. Invasive fungal infections are responsible for >150 million life-threatening illnesses and 1.5 million annual deaths, and pose a distinct threat among people with underlying conditions or immunodeficiencies, transplant and cancer patients. Amongst these fungal pathogens, Candida species are amongst the leading cause of invasive infections and the fourth most common cause of hospital-acquired bloodstream infections. There are limited therapeutic options for treating Candida infections and other fungal diseases, and treatment is further hindered by the evolution of resistance to antifungal therapies, which is frequently observed amongst Candida pathogens. One way in which Candida rapidly adapts to antifungal drugs is via large genome rearrangements, including aneuploidies such as trisomies. These chromosomal trisomies are frequently identified in drug-resistant Candida strains, and are responsible for conferring resistance, although the precise mechanism by which these trisomies lead to resistance is poorly understood. Here, we propose a novel and innovative approach to dissecting the genetic mechanisms underlying aneuploidy-linked antifungal drug resistance in Candida. Using CRISPR activation (CRISPRa)-based overexpression techniques, we will build and screen large libraries of overexpression strains to identify key genes that, when overexpressed, confer increased resistance to diverse antifungal agents. We will validate and follow up on these factors in order to characterize their role in antifungal drug resistance. Together this work will help characterize the fundamental genetic mechanisms by which important fungal pathogens adapt and evolve resistance to antifungal drugs.