Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.
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.
Cadwell
Ken
K
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Patel
Khushbu K
KK
Maloney
Nicole S
NS
Liu
Ta-Chiang
TC
Ng
Aylwin C Y
AC
Storer
Chad E
CE
Head
Richard D
RD
Xavier
Ramnik
R
Stappenbeck
Thaddeus S
TS
Virgin
Herbert W
HW
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
C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma