Cell
Volume 141, Issue 7, 25 June 2010, Pages 1135-1145
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Article
Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine

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Summary

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 TNFα and IFNγ 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.

Highlights

► Mice with mutations in the Crohn's disease gene Atg16L1 display intestinal disease ► Disease requires murine norovirus (MNV) infection together with Atg16L1 mutation ► Viral triggering of disease is dependent on virus strain and timing of infection ► Disease in response to mucosal injury involves cytokines and commensal bacteria

HUMDISEASE
MOLIMMUNO
MICROBIO

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