Characterization of a commensal enteric virus

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

SUMMARY Crosstalk between immune cells and the epithelium protects the intestinal barrier from infectious and non- infectious threats. Elucidating the signals that mediate this cellular crosstalk is necessary to improve our understanding of diseases associated with barrier dysfunction, such as Crohn's disease (CD), a major type of inflammatory bowel diseases (IBD). We previously established a model to investigate how a commensal and otherwise beneficial virus induces immune-mediated damage in a genetically susceptibility host. Infection of Atg16L1 mutant mice with murine norovirus (MNV) inhibits the function and viability of Paneth cells, antimicrobial epithelial cells in the gut. Tissue sections and intestinal organoids derived from CD patients harboring the ATG16L1 risk variant display similar Paneth cell defects. Thus, we have been using the MNV infection model to examine how environmental factors cause epithelial defects associated with intestinal disease. In preliminary data, we found that MNV inhibits secretion of a unique anti-inflammatory effector by T cells that we identified as apoptosis inhibitor 5 (API5). Our data further suggest that API5 prevents inflammatory cell death (necroptosis) of Paneth cells that are defective in the cell biological process of autophagy due to Atg16L1 mutation. The objective of this proposal is to investigate the epithelial-intrinsic and -extrinsic mechanisms that underlie these observations. We will determine how: (1) ATG16L1 and autophagy prevent necroptosis in the intestinal epithelium, (2) API5 secretion by T cells is regulated in response to viral infection, and (3) extracellular API5 exerts protective functions. By investigating this virus-host susceptibility gene interaction, we anticipate identifying new mechanisms involved in intercellular communication and epithelial resilience to injury, thereby improving our understanding of immune-epithelial crosstalk during health and disease.