Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine

Cell. 2010 Jun 25;141(7):1135-45. doi: 10.1016/j.cell.2010.05.009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy-Related Proteins
  • Carrier Proteins / genetics*
  • Crohn Disease / genetics*
  • Crohn Disease / pathology
  • Crohn Disease / virology*
  • Gene Expression Profiling
  • Genetic Predisposition to Disease*
  • Humans
  • Ileum / pathology*
  • Interferon-gamma / metabolism
  • Mice
  • Norovirus*
  • Paneth Cells / metabolism
  • Paneth Cells / virology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Atg16l1 protein, mouse
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma

Grant support