PROJECT SUMMARY The human gut microbiome harbors microbes with the capacity to cause infection or drive pathogenic inflammation. Immune status often determines risk for microbiome-associated disease, which is typically attributed to immune impacts on microbial community composition. But pathogenic or commensal lifestyles can also be dynamically regulated within individual microbes, and there is far less understood about immune impacts on microbial inherent pathogenic potential. Candida albicans is a morphologically and transcriptionally dynamic commensal fungus that can cause life-threatening infections and exacerbate pathogenic inflammation. The ability for C. albicans to cause disease depends on its phenotypic state. Of particular importance is the formation of hyphae, which are elongated cells specialized for adherence and invasion, and promote disease in both infection and inflammatory settings. Immune status is crucial for determining risk for C. albicans-associated disease and both immune deficiencies and active inflammation are linked to C. albicans pathogenesis. However, the role of immune environment on in vivo C. albicans pathogenic potential is not well understood. Here, I will investigate the impact of two human relevant immune environments on C. albicans pathogenic potential. Project 1 will focus on IgA regulation of C. albicans biology. Anti-C. albicans IgA antibodies are found in the gut of most people, and I previously found that C. albicans hyphae and associated effectors are heavily targeted by IgA during colonization. In mouse models, IgA targeting is associated with reduced hyphae and reduced capacity to exacerbate colitis. Here, I will interrogate mechanisms by which IgA regulates C. albicans biology in vivo using a mouse colonization model that permits investigation of immediate regulatory impacts of IgA targeting on C. albicans biology. Using this model, I will interrogate IgA impacts on C. albicans morphology and gene expression, which will include single cell transcriptional profiling to investigate gene expression in individual IgA-targeted cells. The goal of Project 2 is to define the impacts of inflammation on C. albicans pathogenic potential. Evidence from human IBD studies and mouse models of colitis suggest that this fungus exploits inflammation to bloom and perpetuate disease. Here, I will use a mouse model of intestinal colitis to define inflammation-dependent impacts on C. albicans morphology and transcriptional profile, with the goal of defining C. albicans pathways responsible for disease exacerbation. This proposal will reveal fundamental mechanisms by which immune environment regulates C. albicans biology and advance our understanding of how C. albicans becomes pathogenic in certain people. Broadly, these efforts will provide a foundation for our long-term goal of identifying targeted therapeutic strategies to prevent commensal C. albicans reservoirs from causing disease.