Modulation of host metabolism by a persistent enteric virus

持久性肠道病毒对宿主代谢的调节

• 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
• 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

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.

项目摘要 哺乳动物肠道的细菌微生物组在许多过程中具有必不可少的作用 托管生存，包括发酵，肠发展，免疫教学以及通过可溶性 介体，其他器官系统的发展。营养不良与多种病理有关， 包括代谢综合征和非酒精性脂肪肝病（NAFLD）。关于 哺乳动物肠道病毒种群的影响，肠道病毒蛋白与 已显示宿主代谢功能。诺如病毒是小 +RNA病毒，可以建立持续的肠 小鼠和人类的感染，并作为肠粘膜病毒宿主相互作用的模型。 我们实验室的先前实验表明，诺如病毒（MNV）感染可以概括一些 共生菌群在消耗的小鼠中的关键功能。值得注意的是，这些影响传播 在整个肠道中，不仅限于回肠中的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 器官，例如肝脏，类似于肠道细菌。我们发现MNV感染的小鼠有改变 肝脏中的代谢剖面和独特的转录特征，这两者都指向增加 氧化应激和炎症信号传导。这些变化导致饮食模型的加剧 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结果 临床相关的肝病模型。该提议的目的是获得机械洞察力的洞察力 发生。 在该奖学金提案中，我的目标是1）确定活性氧增加在MNV-的作用 介导的代谢变化，2）确定负责MNV影响的免疫信号通路 肝脏和3）确定代谢表型需要哪些病毒因子。建立角色 哺乳动物生物学中的肠道病毒对我们对微生物组的理解很重要。而且，诺维利亚 感染在人口中广泛存在，这项研究将强调其作为危险因素的相关性 代谢疾病。