Enteric virus-microbiota interactions

项目摘要/摘要 肠道病毒在哺乳动物的肠道中会遇到大量的微生物，而微生物区系会影响它们的 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区系，而且 微生物区系枯竭减少了肠道病毒的感染，包括脊髓灰质炎病毒、柯萨奇病毒、诺如病毒、 还有一种呼肠孤病毒株，称为T3SA+。然而，最近的研究表明呼肠孤病毒科的成员 在微生物区系效应中，家庭是异常值。例如，轮状病毒感染是由细菌抑制的，而且大多数 测试的呼肠孤病毒株在微生物区系耗尽时增强了复制。有趣的是，一对呼肠孤病毒 菌株只有一种氨基酸不同，但由于微生物区系枯竭而产生相反的影响。微生物区系枯竭 减少菌株T3SA+的复制，但增加菌株T3SA-的复制。这些病毒的区别在于 S1连接蛋白中的脯氨酸-亮氨酸多态性，使唾液酸与T3SA+结合 菌株，但不是T3SA-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。 小鼠细胞嗜性和对宿主先天免疫反应的敏感性。因此，这些同基因病毒提供了一种 前所未有的机会来定义微生物区系如何影响病毒感染。在这部作品中，我们将1)考察 呼肠孤病毒-多聚糖相互作用的特异性，包括与微生物多聚糖的相互作用，2)决定如何 微生物区系促进呼肠孤病毒T3SA+株的感染；3)阐明微生物区系抑制的机制 呼肠孤病毒T3SA-株。这些研究将提供有关微生物区系如何影响肠道的机械性见解。 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.