title: Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.
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 TNFalpha and IFNgamma 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
authors.forename: Khushbu K
authors.initials: KK
authors.lastname: Patel
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Maloney
authors.forename: Ta-Chiang
authors.initials: TC
authors.lastname: Liu
authors.forename: Aylwin C Y
authors.initials: AC
authors.lastname: Ng
authors.forename: Chad E
authors.initials: CE
authors.lastname: Storer
authors.forename: Richard D
authors.initials: RD
authors.lastname: Head
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007082:Ileum / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D029322:Norovirus; D019879:Paneth Cells / Q000378:metabolism / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma