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

By K. Cadwell, Khushbu K. Patel, N. Maloney, Ta-Chiang Liu, Aylwin Ng, C. Storer, R. Head, Ramnik J. Xavier, T. Stappenbeck, Herbert W. Virgin. Cell, 2010

910 citations recorded by the source corpus.

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.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/0ca097336e7419ab3838aa9deae4d4b179470d07

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. D. Tang
2. N. Mizushima
3. R. Kang
4. M. Komatsu
5. Herbert W. Virgin
6. I. Slaninová
7. Michael Lotze
8. H. J. Zeh

In Infectious Diseases

1. Y. Belkaid
2. Dan R. Littman
3. C. Petersen
4. T. Kanai
5. K. Matsuoka
6. K. Honda
7. F. Powrie
8. June L. Round

Citations in the corpus

• Genetics and pathogenesis of inflammatory bowel disease (2011, background): “The landmark findings that gnotobiotic (germ-free) Atg16l1 HM mice lost these Paneth cell anomalies and their sensitivity to dextrate sulphate sodium (DSS)-induced colitis, and that these abnormalities were restored by norovirus infection provide a definitive demonstration of how host–microbial i”
• Intestinal homeostasis and its breakdown in inflammatory bowel disease (2011, background): “The first of these found that the Paneth cell abnormalities present in mice carrying a hypomorphic mutant of the Atg16l1 autophagy gene ( Atg16l HM ) were triggered by persistent infection with an enteric mouse norovirus strain (MNV CR6”
• PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “A causal relationship clearly exists linking environmental factors, ATG16L1 genetic susceptibility, and the development of CD (147), suggesting that the interaction between host defects in autophagy and environmental stressors such as infection may be crucial for the pathogenesis of certain inflamma”
• The Impact of the Gut Microbiota on Human Health: An Integrative View (2012, neutral): “An influential study by Cadwell et al. sheds light on how the virome, genome, and microbiota might be interacting in the development of Crohn's disease (Cadwell et al., 2010).”
• Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome (2019, result): “Further, the concept that a host with genetic susceptibility fails to deal efficiently with invasive bacteria or pathogens due to defects in their pathogen recognition and handling system was supported by a recent study that showed an induction of colitis in ATG16L1 gene-deficient mice, while no col”