Oligoadenylate synthetase (OAS) in intestinal immunity - The oligoadenylate synthetase (OAS) is a family of enzymes that act as RNA sensors in innate immunity. Microbial dsRNA activates OAS synthesis of short linear 2’5’ oligoadenylates, which activate endoribonuclease RNase L, leading to IFN-I signaling and cell death. The antiviral function of the OAS-RNase L pathway has been established decades ago. However, the function of this pathway in bacterial infection and gut tissue homeostasis are poorly understood. The OAS-RNase L pathway genes are highly expressed in intestinal tissues especially epithelial cells in humans and mice. We found that OAS genes are induced in colon biopsies of active ulcerative colitis patients compared to healthy controls. In addition, several de novo heterozygous OAS1 gain-of-function variants are associated with early-onset inflammatory bowel disease in humans. We generated an Oas1a gain- of-function mouse model, which also develop intestinal inflammation that recapitulates the human disease. Therefore, we hypothesize that OAS enzymes are key innate immune sensors of microbial RNA in the intestine to maintain homeostasis, and aberrant activation of the OAS-RNase L pathway leads to IFN-I signaling and cell death resulting in intestinal inflammatory disease. Aim 1 will determine the expression and activity of the OAS pathway in bacteria-infected intestinal epithelial cells, mouse colitis tissue and human colitis biopsy. Aim 2 will characterize the Oas1a gain-of-function mouse intestinal disease. Together, this R21 proposal serves as a significant first step in filling a critical knowledge gap of OAS function in intestinal immunity.
