Characterization of a commensal enteric virus

项目概要 越来越多的证据支持肠道微生物群的细菌成员在宿主防御和多种 免疫疾病，例如炎症性肠病（IBD）。哺乳动物的胃肠道也 携带多种动物病毒。尽管它们无处不在，但其功能和机械后果 病毒在肠道定植超出其作为腹泻病原体的作用尚不清楚。较上届 在该奖项的资助期间，我们开发了鼠诺如病毒（MNV）模型作为易于处理的实验 系统来解决我们知识中的这一重大差距。我们发现 MNV 可以通过以下方式发挥共生病毒的作用： 为宿主提供益处，例如防止继发细菌感染。与此同时，MNV 诱导 Atg16L1 突变小鼠肠道异常，Atg16L1 是一种 IBD 易感基因，参与 在自噬的细胞降解途径中。该提案的主要目标是使用 MNV 模型 确定确定病毒共生体在肠道定植是否会产生有益效果的机制 或对宿主产生不良后果。我们介绍的数据表明，MNV 感染可以显着改善 刚断奶的小鼠免受革兰氏阴性细菌病原体柠檬酸杆菌致命感染的存活率 啮齿动物。我们建议使用该模型来阐明病毒如何诱导 RNA 传感途径 共生体在生命早期被肠道细菌病原体感染期间介导交叉保护，这是一个主要原因 死亡率。与此同时，我们将研究 Atg16L1 突变如何使原本有益的病毒变得 有害的。我们的初步数据表明了 MNV 感染替代抗炎药物的新机制 肠道中的淋巴细胞具有细胞毒性亚群，可诱导潘氏细胞（一种关键的分泌性上皮细胞）坏死性死亡 与人类 IBD 有关的细胞。定义这些过程的机械细节将为我们带来新的见解 肠道病毒共生体的性质，并可能揭示参与解决组织损伤的新途径 与之前在细菌定植过程中检查的结果不同。

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.