权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要一大群微生物，统称为微生物区系，定居在哺乳动物身上。主持人。除了细菌，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，它导致了约20%的儿童腹泻病例在全球范围内，是严重儿童腹泻的主要原因，并与#年毁灭性感染有关。免疫功能受损的宿主。考虑到所有肠道病毒都会遇到肠道微生物区系在穿越哺乳动物的胃肠道时，必须考虑病毒和细菌之间的相互作用影响病毒感染的结果。事实上，在过去的七年里，这一点已经广为人知共生细菌深刻地调节肠道病毒感染。这个应用程序的重点将是影响以小鼠诺如病毒为模型系统，研究诺如病毒对肠道微生物区系的影响。我们最近做了发现共生细菌抑制胃肠道近端的诺沃克病毒感染这种抑制完全依赖于III型干扰素信号。此外，我们还可以拯救通过在食物中添加单一胆汁酸对细菌枯竭小鼠的抑制作用。这些数据导致我们的细菌代谢胆汁酸在近端肠道诱导III型干扰素的工作模式，从而抑制诺如病毒感染。这项提案的主要目标是勾勒出潜在的近端肠道抑制诺如病毒感染的细菌机制。为此，我们将测试初级胆汁酸抑制小鼠近端肠道诺如病毒感染的特殊假设；确定初级胆汁酸是否在体内诱导III型干扰素；并通过以下方式揭示其分子机制哪种初级胆汁酸能产生主要的III型干扰素。我们的发现可以为小说的发展提供参考基于益生元或应用代谢组学的干预。