Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.
Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.
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DOI：
10.1016/j.cell.2010.05.009
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发表时间：
2010-06-25
期刊：
影响因子：
64.5
通讯作者：
Virgin HW
中科院分区：
文献类型：
--
作者：
Cadwell K;Patel KK;Maloney NS;Liu TC;Ng AC;Storer CE;Head RD;Xavier R;Stappenbeck TS;Virgin HW
目前还不清楚为什么只有一小部分携带疾病易感基因的常见风险等位基因的人会患上疾病。在这里，我们证明了一种特定的病毒感染和克罗恩病易感基因Atg16L1突变之间的相互作用诱导小鼠肠道病变。这种病毒加易感基因的相互作用产生异常颗粒包装和独特的基因表达模式在潘氏细胞。此外，对毒性物质葡聚糖硫酸钠诱导的损伤的反应从根本上改变，包括类似克罗恩病的病理学。这些由病毒加易感基因相互作用引发的病理依赖于TNFα和IFNγ，并可通过广谱抗生素治疗预防。因此，我们提供了一个具体的例子，如何病毒加易感基因的相互作用，结合额外的环境因素和肠道细菌，确定携带常见的风险等位基因的炎症性疾病的宿主的表型。
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.
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