NIAID - National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT There is a growing epidemic of immune-mediated diseases affecting pediatric populations. Candida albicans is an opportunistic fungal species that is habitually found as part of the microbiota in humans, particularly as part of a “dysbiotic” perturbed microbiota associated with increased immune-mediate inflammation disease. Clinical observations have found a strong association with C. albicans and inflammatory diseases, though it is unclear if C. albicans initiates inflammation in an already at-risk atopic individual through acute infection, or can directly influence the development of immune responses. C. Albicans can reside within the intestinal microbiota, and exposure to C. albicans in both human and mice results in the anti-C. albicans immunoglobulins, suggesting an antigen specific immune response. This project will ask how intestinal exposure to C. albicans in early life influences the developing immune system, specifically the T cell responses. Fungal species, including C. albicans induce T cell responses that produce the inflammatory cytokine IL-17, also referred to as T helper 17 cells (Th17), and presence of fungal species can induce further microbial dysbiosis within the intestinal microbiota. It is unknown whether the Th17 cells are responding to the C. albicans or dysbiotic bacterial species in the perturbed microbiota. Additionally, animal studies of C. albicans are hampered by a decreased ability to colonize the adult murine intestinal microbiota with C. albicans without antibiotic perturbation. We have developed a model of neonatal C. albicans acquisition where oral administration of C. albicans between postnatal day 7 and 10 results in stable, robust C. albicans colonization, which is associated with microbial dysbiosis, increase in systemic IL17, increase in Th17 cells in the intestine, and disrupted regulatory T cells. To expand upon these findings, we will 1) evaluate the requirement of goblet cell-associated antigen passages in the induction of a lasting IL-17 response during early life, to assess how intestinal antigens inducing IL-17 responses are introduced to the intestinal immune system following C. albicans colonization. Next, we will 2) evaluate the ability of C. albicans to induce specific Th17 cells and increase pathology during psoriasis using tetramers for C. albicans specific cells, and a chemical-contact model of dermatitis. Through these aims we will mechanistically connect preliminary data from our novel animal model to immune perturbations following C. albicans colonization. Following the completion of this project, we will understand the nature of the antigens initiating Th17 cell responses and have a robust platform to assess the consequence of increased Th17 cells and inflammatory responses following C. albicans colonization. This work has important implications in understanding dysbiosis and microbial imprinting of the immune system in early life.
Up to $444K
2028-01-31
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