Defining the role of Nod2 and bacteria in Atg16L1-dependent intestinal disease.

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DESCRIPTION (provided by applicant): Our long-term goal is to understand how genetic susceptibility and environmental factors combine to mediate inflammatory bowel disease. Atg16L1 and Nod2 are two Crohn's disease susceptibility genes that have received much attention because of their critical function in innate immune defense against bacteria. While an essential role for Atg16L1 in autophagy and Nod2 in bacterial recognition have been demonstrated, it is now clear that mutating these molecules have complex and unanticipated consequences at both the cellular and whole organism level. Therefore, it is critical that we examine these susceptibility genes in the context of intestinal disease to interpret the recent studies that are revealing new downstream functions and pathways. We previously demonstrated that Atg16L1 mutant mice (Atg16L1HM) develop intestinal abnormalities when infected with the mouse norovirus MNV. These abnormalities include the generation of Crohn's-like pathologies when MNV-infected Atg16L1HM mice are injured with the chemical DSS. Remarkably, we have now found that development of these pathologies depends on both commensal bacteria and Nod2. When Atg16L1HM mice are treated with antibiotics or crosed to Nod2 knockout mice, they are protected from intestinal disease induced by MNV and DSS treatment. Given the current challenge in the field in defining Nod2 function and the great interest in understanding commensal bacteria, we will take advantage of these observations to gain insight into mucosal immunity and Crohn's disease pathogenesis. In this proposal, we will test a model in which Nod2 senses specific intestinal bacteria to mediate inflammation in Atg16L1HM mice. We will also determine if the Nod2 frameshift mutation (Nod2fs) associated with Crohn's disease is similar or distinct to Nod2 deletion in the presence of Atg16L1 mutation since this information will have important implications for gene-gene interactions in inflammatory diseases. We will address these issues with the following specific aims: (1) Identify the Nod2 signaling pathway that is responsible for Crohn's-like pathologies in Atg16L1HM mice, (2) Define the specific bacterial population required for disease in Atg16L1HM mice, and (3) Compare the effect of Nod2 deletion and Nod2fs expression in intestinal inflammation. We have a unique opportunity to characterize two susceptibility genes of great interest and the commensal bacterial flora in a multi-hit disease model that recreates pathologies similar to those observed in patients.