Suppression of Enteric Norovirus Infection by Microbiota-Regulated Bile Acids

项目摘要 一大群微生物，统称为微生物区系，定居在哺乳动物身上。 主持人。除了细菌，非致病性和致病性病毒也通过胃肠道进入宿主。的 临床上特别重要的是诺如病毒，它导致了约20%的儿童腹泻病例 在全球范围内，是严重儿童腹泻的主要原因，并与#年毁灭性感染有关。 免疫功能受损的宿主。考虑到所有肠道病毒都会遇到肠道微生物区系 在穿越哺乳动物的胃肠道时，必须考虑病毒和细菌之间的相互作用 影响病毒感染的结果。事实上，在过去的七年里，这一点已经广为人知 共生细菌深刻地调节肠道病毒感染。这个应用程序的重点将是影响 以小鼠诺如病毒为模型系统，研究诺如病毒对肠道微生物区系的影响。我们最近做了 发现共生细菌抑制胃肠道近端的诺沃克病毒感染 这种抑制完全依赖于III型干扰素信号。此外，我们还可以拯救 通过在食物中添加单一胆汁酸对细菌枯竭小鼠的抑制作用。这些数据导致我们的 细菌代谢胆汁酸在近端肠道诱导III型干扰素的工作模式， 从而抑制诺如病毒感染。这项提案的主要目标是勾勒出潜在的 近端肠道抑制诺如病毒感染的细菌机制。为此，我们将测试 初级胆汁酸抑制小鼠近端肠道诺如病毒感染的特殊假设；确定 初级胆汁酸是否在体内诱导III型干扰素；并通过以下方式揭示其分子机制 哪种初级胆汁酸能产生主要的III型干扰素。我们的发现可以为小说的发展提供参考 基于益生元或应用代谢组学的干预。

Project Summary An immense population of microorganisms, collectively referred to as the microbiota, colonizes the mammalian host. In addition to bacteria, nonpathogenic and pathogenic viruses enter hosts via the gastrointestinal tract. Of particular clinical importance are noroviruses, which are responsible for ~20% of pediatric diarrheal cases globally, are the leading cause of severe childhood diarrhea, and are associated with devastating infections in immunocompromised hosts. Considering that all enteric viruses encounter the intestinal microbiota as they traverse the mammalian gastrointestinal tract, it is imperative to consider how virus-bacteria interactions may impact the outcome of viral infections. Indeed, over the past seven years it has become well-established that commensal bacteria profoundly regulate enteric virus infections. The focus of this application will be the influence of the intestinal microbiota on noroviruses, using murine norovirus as a model system. We have recently discovered that commensal bacteria suppress norovirus infection of the proximal region of the gastrointestinal tract, and that this inhibition is entirely dependent on type III interferon signaling. Furthermore, we can rescue inhibition in bacteria-depleted mice by supplementing their chow with a single bile acid. These data lead to our working model that bacterially metabolized bile acids prime type III interferon induction in the proximal gut, thereby inhibiting norovirus infection. The main objective of this proposal is to delineate the underlying mechanism for bacterial suppression of norovirus infection in the proximal gut. To this end, we will test the specific hypothesis that primary bile acids suppress murine norovirus infection of the proximal gut; determine whether primary bile acids prime type III interferon induction in vivo; and uncover the molecular mechanism by which primary bile acids prime type III interferon production. Our findings could inform development of novel interventions based on prebiotics or applied metabolomics.