Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.05.009 Byline: Ken Cadwell (1), Khushbu K. Patel (1), Nicole S. Maloney (1), Ta-Chiang Liu (1), Aylwin C.Y. Ng (3)(4), Chad E. Storer (5), Richard D. Head (5), Ramnik Xavier (3)(4), Thaddeus S. Stappenbeck (1), Herbert W. Virgin (1)(2)(6) Keywords: HUMDISEASE; MOLIMMUNO; MICROBIO Abstract: It is unclear why disease occurs in only a small proportion of persons carrying common risk alleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologies in mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging and unique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxic substance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects of Crohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNF[alpha] and IFN[gamma] and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype of hosts carrying common risk alleles for inflammatory disease. Author Affiliation: (1) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA (2) Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA (3) Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA (4) Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA (5) Inflammation and Immunology Research Unit, Pfizer Global Research and Development, St. Louis, MO 63017, USA (6) Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, St. Louis, MO 63110, USA Article History: Received 9 December 2009; Revised 26 February 2010; Accepted 19 April 2010 Article Note: (miscellaneous) Published: June 24, 2010