Enteric virus-microbiota interactions

项目总结/摘要 肠道病毒在哺乳动物肠道中遇到大量微生物，微生物群影响它们的生长。 感染效率先前的研究表明，大多数肠道病毒都受益于微生物群， 微生物群耗竭减少肠道病毒的感染，包括脊髓灰质炎病毒，柯萨奇病毒，诺如病毒， 和一种叫T3 SA+的呼肠孤病毒。然而，最近的研究表明，呼肠孤病毒科的成员 家庭是微生物群效应的离群值。例如，轮状病毒感染被细菌抑制，并且大多数 测试的呼肠孤病毒株在微生物群耗尽时具有增强的复制。有趣的是，一对呼肠孤病毒 菌株的差异在于单个氨基酸，但具有与微生物群消耗相反的效果。微生物群耗竭 减少菌株T3 SA+的复制，但增加菌株T3 SA-的复制。这些病毒的区别在于 s1附着蛋白中的脯氨酸-亮氨酸多态性，其赋予唾液酸与T3 SA+结合 菌株，但不是T3 SA-菌株。最近的研究表明，这两种呼肠孤病毒株在肠道中也存在差异， 细胞嗜性和对宿主先天免疫应答的敏感性。因此，这些同基因病毒提供了 前所未有的机会来确定微生物群如何影响病毒感染。在这项工作中，我们将1）检查 呼肠孤病毒-聚糖相互作用的特异性，包括与微生物聚糖的相互作用，2）确定如何 微生物群促进呼肠孤病毒株T3 SA+的感染，和3）阐明微生物群抑制的机制 呼肠孤病毒株T3 SA-。这些研究将为微生物群如何影响肠道菌群提供机制见解。 肠道复杂环境中的病毒感染。

PROJECT SUMMARY/ABSTRACT Enteric viruses encounter a vast array of microbes in the mammalian intestine, and microbiota influence their infection efficiency. Previous work has shown that most enteric viruses benefit from the microbiota, and microbiota depletion reduces infection with enteric viruses including poliovirus, coxsackievirus, noroviruses, and one strain of reovirus called T3SA+. However, recent studies indicate that members of the Reoviridae family are outliers in microbiota effects. For example, rotavirus infection is inhibited by bacteria, and most tested strains of reovirus have enhanced replication upon microbiota depletion. Interestingly, a pair of reovirus strains differ by a single amino acid but have opposing effects from microbiota depletion. Microbiota depletion decreases replication of strain T3SA+ but increases replication of strain T3SA-. These viruses differ by a proline-leucine polymorphism in the s1 attachment protein, which confers sialic acid binding to the T3SA+ strain but not the T3SA- strain. Recent studies indicate that these two reovirus strains also differ in intestinal cell tropism and sensitivity to host innate immune responses in mice. Thus, these isogenic viruses provide an unprecedented opportunity to define how microbiota influence viral infection. In this work we will 1) examine the specificity of reovirus-glycan interactions including interactions with microbial glycans, 2) determine how microbiota facilitate infection with reovirus strain T3SA+, and 3) elucidate mechanisms of microbiota inhibition of reovirus strain T3SA-. These studies will provide mechanistic insight into how microbiota influence enteric virus infection in the complex environment of the intestine.