8th Annual BMRP Investigator Meeting - Abstract

 

Ken Cadwell^1,b, Khushbu K. Patel¹, Nicole Maloney¹, Ta-Chiang Liu¹, Aylwin C.Y. Ng³, Chad E. Storer⁴, Richard D. Head⁴, Ramnik Xavier³, Thaddeus S. Stappenbeck¹ and Herbert W. Virgin^1,2,5,a

¹Department of Pathology and Immunology, ²Department of Molecular Microbiology, Washington University School of Medicine (St. Louis, Missouri, U.S.A.); ³Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School (Boston, Massachusetts, U.S.A.); ⁴Inflammation and Immunology Research Unit, Pfizer Global Research and Development; ⁵Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (St. Louis, Missouri, U.S.A.)

 

Genetic studies have identified many polymorphisms that confer increased susceptibility to Crohn’s disease. However, most individuals carrying the risk polymorphism of a susceptibility gene do not acquire the disease. We demonstrate that an interaction between virus infection and a mutation in the disease susceptibility gene Atg16L1 induces unexpected intestinal abnormalities in mice. This virus-plus-susceptibility gene interaction generated striking abnormalities in Paneth cells, similar to observations we recently made in human Crohn’s disease patients carrying the risk allele of ATG16L1. Further, in the presence of virus and Atg16L1 mutation, the intestinal injury response was fundamentally altered to include pathologies resembling aspects of Crohn’s disease. These intestinal abnormalities were dependent on TNFα and IFNγ, and were prevented by treatment with broad spectrum antibiotics. Virus-plus-susceptibility gene interactions may, in combination with injury and bacteria, contribute to inflammatory bowel disease in hosts carrying common risk polymorphisms.