Characterization of a commensal enteric virus

项目总结 越来越多的证据支持肠道微生物区系中的细菌成员在宿主防御和各种 免疫紊乱，如炎症性肠病(IBD)。哺乳动物的胃肠道也 有各种各样的动物病毒。尽管它们无处不在，但其功能性和机械性后果 除了作为腹泻病原体的作用外，病毒在肠道的定植作用还不清楚。在上一次中 在此奖项的资助期内，我们开发了小鼠诺沃克病毒(MNV)模型，作为一种易于处理的实验 系统来解决我们知识中的这一重大差距。我们发现MNV可以作为一种共生病毒发挥作用 为宿主提供好处，例如防止二次细菌感染。与此同时，MNV 参与IBD易感基因Atg16L1突变的小鼠肠道功能异常 在自噬的细胞降解途径中。这项提案的主要目标是使用MNV模式 确定确定病毒共生体在肠道定植是否有益的机制 或对宿主不利的后果。我们介绍的数据表明，MNV感染可以显著改善 革兰氏阴性细菌柠檬酸杆菌对新生断奶小鼠致死性感染的存活 齿状骨。我们建议使用这个模型来阐明病毒是如何诱导rna感应通路的。 共生体在早期肠道细菌感染中介导交叉保护，肠道细菌病原体是主要原因 死亡的威胁。同时，我们将研究Atg16L1突变如何使原本有益的病毒变得 有害的。我们的初步数据提示MNV感染替代抗炎的一种新机制 肠道中含有细胞毒性亚群的淋巴细胞可导致关键的分泌上皮细胞潘氏细胞的坏死性死亡 与人类IBD有关的细胞。定义这些过程的机械性细节将产生对 肠道中病毒共生体的性质，并可能揭示参与组织损伤解决的新途径 与以前在细菌定植期间检查的那些不同。

PROJECT SUMMARY Accumulating evidence support the role of bacterial members of the gut microbiota in host defense and a variety of immune disorders, such as inflammatory bowel disease (IBD). The mammalian gastrointestinal tract also harbors diverse animal viruses. Despite their ubiquitous presence, the functional and mechanistic consequences of intestinal colonization by viruses beyond their role as diarrheal pathogens has been unclear. Over the previous funding periods of this award, we developed the murine norovirus (MNV) model as a tractable experimental system to address this major gap in our knowledge. We found that MNV can function as a symbiotic virus by providing benefits to the host, such as protection against secondary bacterial infection. At the same time, MNV induces intestinal abnormalities in mice with a mutation in Atg16L1, an IBD susceptibility gene that participates in the cellular degradative pathway of autophagy. The main objective of this proposal is to use the MNV model to define the mechanisms that determine whether intestinal colonization by a viral symbiont leads to beneficial or adverse outcomes for the host. We introduce data showing that MNV infection can significantly improve survival of newly weaned mice from lethal infection by the Gram-negative bacterial pathogen Citrobacter rodentium. We propose to use this model to elucidate how RNA sensing pathways are induced by a viral symbiont to mediate cross-protection during early-life infection by an enteric bacterial pathogen, a leading cause of mortality. In parallel, we will investigate how Atg16L1 mutation makes an otherwise beneficial virus become harmful. Our preliminary data suggests a novel mechanism in which MNV infection replaces anti-inflammatory lymphocytes in the gut with cytotoxic subsets that induce necrotic death of Paneth cells, a key secretory epithelial cell implicated in human IBD. Defining the mechanistic details of these processes will yield new insight into the nature of a viral symbiont in the gut, and may reveal new pathways involved in the resolution of tissue injury that are distinct from those previously examined during bacterial colonization.