Suppression of Enteric Norovirus Infection by Microbiota-Regulated Bile Acids

通过微生物群调节的胆汁酸抑制肠道诺如病毒感染

基本信息

批准号：
10517512
负责人：
Stephanie M Karst
金额：
$ 53.74万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-25 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10517512
关键词：
Anti-Inflammatory Agents Bacteria Bacterial Model Bile Acids Binding Biological Models Calicivirus Infections Childhood Clinical Data Development Diarrhea Distal Enteral Gastrointestinal tract structure Human poliovirus Immune Immune response Immunity Immunocompromised Host In Vitro Infection Interferons Intervention Intestines Lead Link Literature Mediating Metabolic Metabolic Biotransformation Molecular Mouse Mammary Tumor Virus Mus Norovirus Outcome Pathogenesis Play Population Process Production Publishing Regulation Reovirus Role Rotavirus Signal Transduction Surface Testing Therapeutic Time Viral Virus Virus Diseases Work cell type combinatorial commensal bacteria diarrheal disease enteric virus infection gut microbiota in vivo insight metabolomics microbiota microorganism novel novel therapeutics pathogenic virus prebiotics receptor regional difference response

项目摘要

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.

项目概要哺乳动物中栖息着大量的微生物，统称为微生物群。主持人。除了细菌之外，非致病性和致病性病毒也通过胃肠道进入宿主。的临床上特别重要的是诺如病毒，大约 20% 的儿童腹泻病例是由诺如病毒引起的在全球范围内，它们是严重儿童腹泻的主要原因，并与毁灭性感染有关免疫功能低下的宿主。考虑到所有肠道病毒在传播过程中都会遇到肠道微生物群当病毒穿过哺乳动物胃肠道时，必须考虑病毒与细菌的相互作用如何影响影响病毒感染的结果。事实上，在过去的七年里，人们已经公认：共生细菌深刻调节肠道病毒感染。此应用程序的重点将是影响力使用鼠诺如病毒作为模型系统，研究诺如病毒的肠道微生物群。我们最近有发现共生细菌抑制胃肠道近端区域的诺如病毒感染道，并且这种抑制完全依赖于 III 型干扰素信号传导。此外，我们还可以拯救通过给小鼠的食物补充单一胆汁酸来抑制细菌耗尽的小鼠。这些数据导致我们细菌代谢胆汁酸在近端肠道诱导 III 型干扰素的工作模型，从而抑制诺如病毒感染。该提案的主要目标是描绘基本的近端肠道细菌抑制诺如病毒感染的机制。为此，我们将测试初级胆汁酸抑制近端肠道的小鼠诺如病毒感染的具体假设；决定初级胆汁酸是否能在体内诱导III型干扰素；并揭示其分子机制其中初级胆汁酸素产生III型干扰素。我们的发现可以为小说的开发提供信息基于益生元或应用代谢组学的干预措施。