A Genetics Approach to Candida albicans Gastrointestinal Colonization Resistance

About This Grant

PROJECT SUMMARY/ABSTRACT 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. 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 to catabolize available simple sugars in the colon (sorbitol, for example). This will be explored in Aim 1 using C. albicans mutants that are unable to catabolize sorbitol in multiple murine and in vitro models. Antibiotics increase the amount of oxygen available in the colon, and oxygen availability seems vital for C. albicans to colonize the colon. Even though 5-ASA reduces gastrointestinal colonization of C. albicans, it remains unknown if 5-ASA prevents development of invasive candidiasis. It is also unknown if C. albicans oxygen availability in the colon is required for dissemination. In Aim 2, we will answer this question using a C. albicans dissemination model using the cancer therapeutic cyclophosphamide, while also evaluating if C. albicans aerobic respiration is required for dissemination utilizing a C. albicans mutant with impaired aerobic respiration. 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.