Modulation of host metabolism by a persistent enteric virus

持久性肠道病毒对宿主代谢的调节

基本信息

批准号：
10063430
负责人：
Eugene Rudensky
金额：
$ 3.7万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063430
关键词：
Acetaminophen Acetylcysteine Acute Affect Automobile Driving Bacteria Biology Chimera organism Clinical Communities Cues Development Diet Disease Disease model Elements Enteral Etiology Feces Fellowship Fermentation Gastrointestinal tract structure Gene Expression Gene Expression Profile Genes Germ-Free Goals Gut Mucosa Hepatic Hepatotoxicity Human Immune Immune signaling Immunity Immunocompetent Individual Infection Inflammatory Instruction Interferons Intestinal Mucosa Intestines Knock-out Link Liver Liver diseases Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic syndrome Metabolism Modeling Mus Norovirus Organ Outcome Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Phenotype Physiology Plasma Play Population Population Research Portal vein structure Process Production RNA Viruses Reactive Oxygen Species Research Risk Factors Role Services Severities Signal Pathway Signal Transduction Small RNA T cell response Testing Tissues Viral Viral Genome Virus Virus Diseases Work bacteriome biological adaptation to stress body system clinically relevant clinically significant commensal microbes cytokine dysbiosis enteric infection experimental study gut bacteria ileum immunoregulation insight intestinal injury lipid metabolism mesenteric lymph node metabolic phenotype metabolic profile metabolomics microbiome microbiome research microbiota non-alcoholic fatty liver disease particle receptor transcriptome sequencing transcriptomics virome virus host interaction

项目摘要

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.

项目概要哺乳动物肠道的细菌微生物组在许多重要的过程中发挥着不可或缺的作用宿主生存，包括发酵、肠道发育、免疫指令，以及通过可溶性介体，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）。人们对它知之甚少哺乳动物肠道病毒种群的影响，并且肠道病毒组和肠道病毒组之间不存在联系宿主代谢功能已显示。诺如病毒是小+RNA病毒，可以建立持久的肠道小鼠和人类感染，并作为肠粘膜病毒与宿主相互作用的模型。我们实验室之前的实验表明，鼠诺如病毒 (MNV) 感染可以重现一些微生物群耗尽的小鼠中共生菌群的关键功能。值得注意的是，这些影响被广泛传播整个肠道，并且不限于回肠中的 MNV 复制生态位。因为 MNV 能够间接影响肠道生理学，我们假设它的存在也会对其他肠道生理产生影响肝脏等器官，其方式与肠道细菌类似。我们发现感染 MNV 的小鼠的基因发生了改变代谢特征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传导。这些变化导致饮食模式的恶化非酒精性脂肪肝。这提供了第一个证据，证明局部肠道病毒感染可以显着改变结果临床相关肝病模型的建立。该提案的目标是获得机制上的洞察力发生。在本研究金提案中，我的目标是 1) 确定活性氧物质增加在 MNV- 介导的代谢变化，2) 确定负责 MNV 对肝脏，3) 确定代谢表型需要哪些病毒因子。确立该机构的角色哺乳动物生物学中的肠道病毒组对于我们了解微生物组非常重要。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。