Investigating the role of a2A adrenergic receptor in C. difficile infection pathology 9096

Abstract Description Clostridioides difficile infection (CDI) is the leading healthcare-associated infection in the U.S. CDI pathology is largely attributed to toxins A (TcdA) and B (TcdB) produced by C. difficile, which cause colon tissue damage and inflammation. Recently, the sympathetic nervous system has been found to exacerbate CDI inflammation. Specifically, 6-OHDA-induced sympathectomy, α2A adrenergic receptor (α2AAR) blockers, and Adra2a knockout (KO) mice all show improved colonic barrier integrity and survival during acute CDI. However, the precise mechanism by which α2AAR exacerbates CDI pathology remains unclear despite the potential to inform novel therapeutics development. The intestinal epithelium is a site of α2AAR expression, leading to our hypothesis that the α2AAR in the epithelium has a direct impact on host cell sensitivity to C. difficile toxins. Using a cell rounding toxicity assay, we show that norepinephrine—the ligand of α2AAR, does not alter sensitivity to TcdB. Similarly, the α2AR blocker RX821002 failed to protect the cells from TcdB. These preliminary results suggest that α2AAR does not influence intestinal epithelium susceptibility to TcdB as part of its role in driving CDI pathology. Future studies will use different cell lines and in vivo models to validate these results. Additionally, to test the involvement of epithelial and immune cells in α2AAR-driven CDI pathology, tissue-specific Adra2a conditional KO and bone marrow transplants will be performed. Funding Sources Supported by NIH grants R01 AI152477; R01 AI124214, and Univ. of Virginia Cancer Center Outstanding International Student Fellowship. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)