Modulation of host metabolism by a persistent enteric virus

项目摘要 哺乳动物肠道的细菌微生物组在许多重要的过程中具有不可或缺的作用。 宿主生存，包括发酵，肠道发育，免疫指令，并通过可溶性 介体，其他器官系统的发育。生态失调与许多病理学有关， 包括代谢综合征和非酒精性脂肪肝（NAFLD）。关于这一点，我们所知甚少。 哺乳动物肠道病毒群的影响，肠道病毒组和 已经显示了宿主代谢功能。诺如病毒是一种小+RNA病毒，可以建立持续的肠道 在小鼠和人类中的感染，并作为在肠粘膜的病毒-宿主相互作用的模型。 我们实验室以前的实验确定，小鼠诺如病毒（MNV）感染可以重演一些 肠道植物群在微生物群耗竭小鼠中的关键功能。值得注意的是，这些影响被传播 在整个肠中，并且不限于回肠中的MNV复制小生境。因为MNV能够 间接影响肠道生理学，我们假设它的存在也会影响其他 器官，如肝脏，以类似于肠道细菌的方式。我们发现，MNV感染的小鼠有一个改变， 代谢谱和肝脏中独特的转录特征，两者都表明， 氧化应激和炎症信号。这些变化导致了一种饮食模式的恶化， NAFLD。这提供了第一个证据表明，局部肠道病毒感染可以显着改变的结果 临床相关的肝病模型。本提案的目标是从机制上了解这一点， 发生。 在这个奖学金的建议，我的目标是1）确定增加的活性氧在MNV的作用- 介导的代谢变化，2）确定负责MNV对免疫系统的影响的免疫信号传导途径。 肝脏，和3）确定哪些病毒因子是代谢表型所需的。确定联合国的作用 哺乳动物生物学中的肠道病毒组对我们理解微生物组很重要。此外，诺如病毒 感染在人群中广泛存在，这项研究将强调其作为危险因素的相关性 代谢性疾病

Project Summary The bacterial microbiome of the mammalian gut has an indispensable role in a number of processes important to host survival, including fermentation, intestinal development, immune instruction and, through soluble mediators, the development of other organ systems. Dysbiosis has been linked to a number of pathologies, including metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Much less is known about the influence of the viral population of the mammalian gut, and no existing links between the enteric virome and host metabolic function have been shown. Norovirus is small +RNA virus that can establish persistent enteric infections in mice and humans and serves as a model of virus-host interactions at the intestinal mucosa. Previous experiments from our lab established that Murine Norovirus (MNV) infection can recapitulate some of the key functions of the commensal flora in microbiota-depleted mice. Remarkably, these effects were spread throughout the intestine and were not limited to the MNV replication niche in the ileum. Because MNV is able to influence intestinal physiology indirectly, we hypothesized that its presence can also have an effect on other organs such as the liver, in a manner similar to gut bacteria. We found that MNV-infected mice have an altered metabolic profile and a distinct transcriptional signature in the liver, both of which pointed to an increase in oxidative stress and inflammatory signaling. These changes resulted in an exacerbation of a dietary model of NAFLD. This provides the first evidence that localized enteric viral infection can significantly alter the outcome of a clinically relevant liver disease model. The goal of this proposal is to gain mechanistic insight into how this occurs. In this fellowship proposal, I aim to 1) determine the role of increased reactive oxygen species in MNV- mediated metabolic changes, 2) identify the immune signaling pathways responsible for MNV effects on the liver, and 3) determine which viral factors are required for the metabolic phenotype. Establishing the role of the gut virome in mammalian biology is important to our understanding of the microbiome. Moreover, noroviral infection is widespread in the human population and this research will highlight its relevance as a risk factor in metabolic diseases.