Restoring Gastrointestinal Microbiota-Host Interactions to Prevent Invasive Candidiasis

About This Grant

PROJECT SUMMARY The World Health Organization classified Candida albicans as a critical pathogen warranting increased research and development needs. C. albicans is the most common etiology of invasive candidiasis, which occurs when C. albicans enters the blood stream (candidemia) and disseminates throughout the body (i.e. the liver and spleen) where mortality approaches 50%. People with hematologic malignancies have the highest risk for invasive candidiasis and Candida spp. expands in the gastrointestinal tract prior to development of invasive disease. This expansion requires antibiotic mediated loss of Candida spp. colonization resistance within the gastrointestinal tract. While antifungal prophylaxis has been used in this population to improve outcomes, there are increasing rates of antifungal resistance along with breakthrough infections despite antifungal prophylaxis demonstrating a critical need for new approaches for prevention and better understanding of how C. albicans colonizes the gastrointestinal tract. We recently demonstrated the importance of oxygen availability in allowing C. albicans to colonize the gastrointestinal tract and identified that the inflammatory bowel disease drug, 5-aminosalicyclic acid (5-ASA), restores colonization resistance to C. albicans. We hypothesize that oxygen availability is necessary for C. albicans to colonize the gastrointestinal tract and subsequently disseminate out of the gastrointestinal track. Even though 5-ASA reduces gastrointestinal colonization of C. albicans, it remains unknown if 5-ASA prevents development of invasive candidiasis. In Aim 1, we will answer this question using a C. albicans dissemination model using the cancer therapeutic cyclophosphamide, while also evaluating the mechanism behind 5-ASA reducing C. albicans in the gastrointestinal tract of mice. Successful completion of these aims will provide mechanistic detail into how the critical pathogen C. albicans colonizes the gastrointestinal tract while simultaneously assessing the novel approach to preventing invasive candidiasis via restoration of gastrointestinal epithelial hypoxia.