Plasma membrane promotes stress resistance and virulence of Candida albicans

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Project Summary The human fungal pathogen Candida albicans is a leading cause of hospital-acquired bloodstream infections and can disseminate to become lethal. 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. The plasma membrane is fundamentally important for these processes, as this essential barrier mediates a wide range of functions that are critical for virulence including cell wall synthesis, secretion of virulence factors, morphogenesis, and nutrient uptake. The importance of the plasma membrane is highlighted by the fact that it is the target for most of the currently used antifungal drugs and many antimicrobial peptides. Therefore, a better understanding of plasma membrane organization and function is needed to facilitate the design of new therapeutic treatments and to increase the effectiveness of current antifungal drugs. To address this gap in knowledge, the Aims are designed to take advantage of recent discoveries to identify novel mechanisms by which the plasma membrane protects C. albicans from stressful conditions in the host. Aim 1 is to define the mechanisms that protect the plasma membrane against the oxidative burst in the host, which can cause a chain reaction of lipid peroxidation that destroys membrane integrity. These studies will leverage our recent identification of a new pathway that protects C. albicans against lipid peroxidation. Aim 2 will define how the PM resists stress caused by HOCl (hypochlorous acid; bleach) that is produced by myeloperoxidase during the neutrophil oxidative burst. Although neutrophils are well known to produce HOCl, little is known about its effects on the plasma membrane or how C. albicans protects against it. Aim 3 is to define how the C. albicans PM plays a key role in resisting copper and cell wall stress, which are also encountered in the phagosome. This aim takes advantage of our discovery that specialized plasma membrane subdomains known as eisosomes or MCC domains promote proper PM architecture needed for resistance to copper and cell wall stress. Defining how the C. albicans plasma membrane resists stress is expected to reveal novel mechanisms of pathogenesis that will aid future studies in development of new therapeutic approaches and increase our understanding of current antifungal drugs to improve the prospects for their more effective use.