Modulation of host metabolism by a persistent enteric virus

项目摘要 哺乳动物肠道中的细菌微生物群在许多重要的过程中起着不可或缺的作用。 对寄主的生存，包括发酵、肠道发育、免疫指示和通过可溶性 调解人，其他器官系统的发展。生物失调与许多病理疾病有关， 包括代谢综合征和非酒精性脂肪肝(NAFLD)。人们对此知之甚少 哺乳动物肠道病毒种群的影响，以及肠道病毒和肠道病毒之间不存在现有联系 宿主的代谢功能已被证明。诺沃克病毒是一种可以建立持久性肠道的小RNA病毒 在小鼠和人类中感染，并作为肠道粘膜病毒与宿主相互作用的模型。 我们实验室以前的实验证明，小鼠诺如病毒(MNV)感染可以概括一些 微生物区系耗竭小鼠的共生菌群的关键功能。值得注意的是，这些影响扩散了。 并不局限于MNV在回肠的复制生态位。因为MNV能够 间接影响肠道生理，我们假设它的存在也会对其他 器官，如肝脏，以类似肠道细菌的方式。我们发现感染MNV的小鼠有一种改变 肝脏中的代谢特征和明显的转录特征，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著改变预后。 一种临床相关的肝病模型。这项提议的目标是机械地洞察这一点 发生。 在这份奖学金提案中，我的目标是：1)确定MNV中增加的活性氧物种的作用- 介导的代谢变化，2)确定免疫信号通路负责的MNV影响在 肝脏，以及3)确定代谢表型所需的病毒因子。确立该组织的角色 肠道病毒组在哺乳动物生物学中对我们理解微生物组很重要。此外，诺如病毒 感染在人群中很普遍，这项研究将强调它作为一种危险因素在 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.