Suppression of Enteric Norovirus Infection by Microbiota-Regulated Bile Acids

项目摘要 大量的微生物，统称为微生物群，在哺乳动物体内定植。 主持人除细菌外，非致病性和致病性病毒通过胃肠道进入宿主。的 特别重要的临床是诺如病毒，约20%的儿童腹泻病例是由诺如病毒引起的 在全球范围内，是严重的儿童腹泻的主要原因，并与破坏性感染有关， 免疫受损的宿主考虑到所有肠道病毒都会遇到肠道微生物群， 通过哺乳动物的胃肠道，必须考虑病毒-细菌相互作用如何可能 影响病毒感染的结果。事实上，在过去的七年里， 肠道细菌深刻地调节肠道病毒感染。这一应用的重点将是影响力 肠道微生物群对诺如病毒的影响，使用鼠诺如病毒作为模型系统。我们最近 发现肠道细菌抑制诺如病毒对胃肠道近端区域的感染， 道，并且这种抑制完全依赖于III型干扰素信号传导。此外，我们还可以拯救 在细菌耗尽的小鼠中通过用单一胆汁酸补充它们的食物来抑制。这些数据导致我们 细菌代谢的胆汁酸在近端肠道中引发III型干扰素诱导的工作模型， 从而抑制诺如病毒感染。本提案的主要目的是阐明 近端肠道中诺如病毒感染的细菌抑制机制。为此，我们将测试 初级胆汁酸抑制近端肠道的鼠诺如病毒感染的特定假设;确定 初级胆汁酸是否引发体内III型干扰素诱导;并通过以下方法揭示其分子机制： 其中初级胆汁酸引发III型干扰素的产生。我们的发现可以为新的开发提供信息。 基于益生元或应用代谢组学的干预措施。

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.