Investigating the Role of Bcr1 in Candida albicans-persistence and pathogenesis in the inflamed gut - PROJECT SUMMARY Inflammatory bowel disease (IBD) is a chronic condition characterized by persistent intestinal inflammation and microbial dysbiosis, including frequent blooms of Candida albicans. While C. albicans typically resides as a commensal in mucosal sites, under IBD conditions it can exacerbate inflammation and contribute to disease severity. The mechanisms by which intestinal inflammation promotes fungal persistence and pathogenicity remain poorly defined. To address this gap, we employed in vivo transcriptional profiling in a DSS-induced colitis mouse model to investigate C. albicans biology during inflammation. RNA sequencing revealed significant upregulation of biofilm-associated genes, including the transcription factor BCR1, which is critical for biofilm formation and fungal pathogenesis in other infection models. Preliminary competition assays further demonstrated that Bcr1 confers a colonization advantage in both laboratory and patient-derived strains, implicating this factor as a novel regulator of fungal fitness in the gut. This project hypothesizes that intestinal inflammation promotes C. albicans biofilm-like growth and that Bcr1 plays a central role in fungal persistence and inflammation in IBD. In Aim 1, we will define the contribution of Bcr1 to fungal colonization, biofilm-like aggregate formation, and host immune responses during DSS-induced colitis, using fluorescence microscopy and in vivo disease severity metrics. In Aim 2, we will investigate downstream targets of Bcr1, focusing on Sap4 and Sap6, which are aberrantly expressed in the absence of Bcr1. Using single and double deletion mutants, we will test whether repression of these proteases contributes to colonization fitness and adaptation to the inflamed gut. All experiments will be conducted under the guidance of my primary sponsor, Kyla Ost, PhD, with co-sponsorship from Marijke Keestra-Gounder, PhD, whose expertise in mucosal immunology provides complementary perspective. I will also consult with my thesis committee for additional support and guidance. My training program includes coursework, journal clubs, and seminars that will broaden my knowledge across fungal biology, immunology, and host-pathogen interactions. Overall, the proposed project and training objectives in this F31 application are designed to prepare me as an independent scientist with a strong foundation in mucosal immunology and microbial-host interactions. Through advanced in vivo and in vitro approaches, rigorous mentorship, and interdisciplinary training, this work will enhance my technical skills, critical thinking, and ability to communicate complex findings. Ultimately, this project will uncover novel mechanisms by which intestinal inflammation promotes fungal persistence and pathogenesis, while equipping me to contribute meaningfully to the field and pursue a career as an impactful, independent investigator.
