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Enteric virus-microbiota interactions

肠道病毒-微生物群相互作用

基本信息

批准号：
10411499
负责人：
Julie K Pfeiffer
金额：
$ 7.77万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411499
关键词：
Acetates Affect Antibiotic Therapy Antibiotics Bacteria Butyrates Cell-Matrix Junction Colon Complex Coxsackie Viruses Data Diet Dietary Fiber Distal Enteral Environment Epithelial Cells Family Family Picornaviridae Gastrointestinal tract structure Gene Expression Genes Germ-Free Goals HDAC4 gene Histone Deacetylase Histone Deacetylase Inhibitor Human Human poliovirus Immune Infection Innate Immune Response Intestines Mediating Metabolic Metabolism Modeling Mouse Mammary Tumor Virus Mus Norovirus Oral Pathogenesis Polysaccharides Propionates Receptor Down-Regulation Regimen Reovirus Role Route Science Small Intestines Source Specificity Surface System Up-Regulation Viral Virus Virus Diseases Virus Replication Volatile Fatty Acids Work enteric virus infection gut microbiota intestinal homeostasis microbial community microbiota oxidation particle transcriptome transcriptome sequencing transmission process tributyrin

项目摘要

Viruses transmitted by the fecal-oral route are among the most common human infections, but little is known about factors that influence transmission and viral replication in the intestine. The gastrointestinal tract is a complex environment and enteric viruses encounter a vast microbial community. Intestinal bacteria promote replication and pathogenesis of enteric viruses in mice, including poliovirus, reovirus, mouse mammary tumor virus, and norovirus. Thus, unrelated viruses from four families benefit from intestinal bacteria, highlighting the importance of understanding virus-microbiota interactions. Microbiota promote replication of enteric viruses through multiple mechanisms, including direct interactions with viral particles that aid attachment and stability, and indirect modulation of the host innate immune response. Although poliovirus and coxsackievirus B3 (CVB3) are two closely related viruses in the Picornaviridae family, our data suggest that microbiota enhance their infection through distinct mechanisms. While inhibition of poliovirus replication requires a potent cocktail of four antibiotics, CVB3 replication is inhibited by much more subtle antibiotic regimens. These results suggest that CVB3 is more reliant on microbiota than poliovirus and that a specific subset of bacteria may be required for efficient CVB3 infection. Bacteria in the colon ferment dietary fiber to produce short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate. SCFAs are among the most abundant molecules in the distal gastrointestinal tract and influence intestinal metabolism and gene expression in ways that could impact enteric virus replication. Recently, we determined that a single bacterial metabolite, butyrate, is sufficient to promote CVB3 replication in microbiota-depleted mice. Our central hypothesis is that bacteria-derived SCFAs promote enteric virus replication by altering host gene expression and intestinal homeostasis. In this work we will 1. Examine the specificity of SCFA-mediated effects on enteric virus replication and 2. Examine how SCFA-mediated changes in host gene expression affect enteric virus replication. Overall, our goal is to use the power of model viruses to understand mechanisms by which bacteria promote enteric virus infection.

通过粪口途径传播的病毒是最常见的人类感染之一，但人们知之甚少关于影响肠道传播和病毒复制的因素。胃肠道是一个复杂的环境和肠道病毒遇到了庞大的微生物群落。肠道细菌促进小鼠肠道病毒的复制和发病机制，包括脊髓灰质炎病毒、呼肠孤病毒、小鼠乳腺肿瘤病毒和诺如病毒。因此，来自四个科的不相关病毒受益于肠道细菌，这凸显了了解病毒-微生物群相互作用的重要性。微生物群促进肠道病毒的复制通过多种机制，包括与有助于附着和稳定性的病毒颗粒的直接相互作用，以及间接调节宿主先天免疫反应。虽然脊髓灰质炎病毒和柯萨奇病毒 B3 （CVB3）是小核糖核酸病毒科中两种密切相关的病毒，我们的数据表明微生物群增强他们通过不同的机制进行感染。虽然抑制脊髓灰质炎病毒复制需要有效的鸡尾酒在四种抗生素中，CVB3 的复制受到更微妙的抗生素治疗方案的抑制。这些结果表明 CVB3 比脊髓灰质炎病毒更依赖微生物群，并且可能需要特定的细菌子集用于有效的 CVB3 感染。结肠中的细菌发酵膳食纤维产生短链脂肪酸 (SCFA) 包括乙酸盐、丙酸盐和丁酸盐。 SCFA 是自然界中最丰富的分子之一远端胃肠道并以可能影响肠道代谢和基因表达的方式影响肠道病毒复制。最近，我们确定单一细菌代谢物丁酸盐足以促进微生物群耗尽的小鼠中的 CVB3 复制。我们的中心假设是细菌来源的 SCFA 通过改变宿主基因表达和肠道稳态来促进肠道病毒复制。在这项工作中我们将 1. 检查 SCFA 介导的对肠道病毒复制影响的特异性，以及 2. 检查如何 SCFA 介导的宿主基因表达变化影响肠道病毒复制。总的来说，我们的目标是使用模型病毒了解细菌促进肠道病毒感染机制的能力。