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

Ken Cadwell, Khushbu K. Patel, Nicole S. Maloney, Ta Chiang Liu, Aylwin C Y Ng, Chad E. Storer, Richard D. Head, Ramnik Xavier, Thaddeus S. Stappenbeck, Herbert W. Virgin

Research output: Contribution to journalArticle

609 Scopus citations

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 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. PaperClip:

Original languageEnglish (US)
Pages (from-to)1135-1145
Number of pages11
JournalCell
Volume141
Issue number7
DOIs
StatePublished - Jun 2010

Keywords

  • Humdisease
  • Microbio
  • Molimmuno

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Cadwell, K., Patel, K. K., Maloney, N. S., Liu, T. C., Ng, A. C. Y., Storer, C. E., Head, R. D., Xavier, R., Stappenbeck, T. S., & Virgin, H. W. (2010). Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine. Cell, 141(7), 1135-1145. https://doi.org/10.1016/j.cell.2010.05.009