Candida albicans is the most common cause of mucosal and systemic fungal infections in humans and is frequently responsible for hospital-acquired bloodstream infections. There is an urgent need to improve the therapeutic management of C. albicans infections, since current antifungal drugs have limited effectiveness and drug-resistant strains are emerging. The pathogenic effects of C. albicans are caused by its ability to grow in the host and disseminate to internal organs. Central to these processes is the plasma membrane, an essential barrier that mediates a broad range of functions that are critical for virulence. These functions include cell wall synthesis, secretion of virulence factors, morphogenesis, and nutrient uptake. The importance of the plasma membrane for virulence is underscored by the fact that it is directly or indirectly the target of the currently used antifungal drugs. Recent studies have revealed that the fungal plasma membrane is divided into distinct subdomains, including the punctate patches termed eisosomes. These 300 nm-sized domains contain integral membrane proteins, such as Sur7, and an adjacent complex of >20 peripheral membrane proteins including Pil1 and Lsp1 that promote formation of eisosomes. Our recent studies showed that Sur7, Pil1, and Lsp1 are the key players in the eisosome, as their mutation causes multiple defects including impaired cell wall synthesis, abnormal morphogenesis, and increased sensitivity to stress, oxidation, and antifungal drugs. Therefore, the Aims of our current proposal are to determine how eisosomes regulate three functions that are required for virulence:
(Aim 1) cell wall synthesis and invasive hyphal morphogenesis, (Aim 2) resistance to different types of stress including copper and high temperature, and (Aim 3) a novel antioxidant pathway we discovered that protects the plasma membrane from oxidation and is needed for virulence. The proposed studies will identify novel drug targets and increase our understanding of the effects of current antifungal drugs. Defining eisosome function in C. albicans will also provide a model for the role of these plasma membrane domains in other pathogenic fungi.
New medical treatments and an aging population are increasing the pool of individuals that are susceptible to lethal systemic infections caused by Candida albicans, the most common human fungal pathogen. Improved therapeutic approaches are needed to meet this escalating problem due to the limitations of current antifungal drugs. The proposed studies on the C. albicans plasma membrane, the essential barrier that surrounds the cell, are expected to improve therapeutic success by providing a better understanding of current antifungal drugs and by identifying new targets for therapeutic intervention.
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