Mechanisms of Reovirus Bloodstream Dissemination

项目摘要 病毒从感染的粘膜部位传播到靶组织和器官是一种免疫反应。 是许多病毒性疾病发病机制的基础步骤。病毒通常使用 血液和淋巴系统作为将病毒递送到器官和组织的途径 在整个身体。虽然血液传播病毒的一般原则是 尽管我们已经了解，但对于控制病毒的病毒和细胞决定因子知之甚少。 通过这些途径传播。本申请中描述的实验的总体目标 是确定病毒通过血液传播的机制和功能后果。工作 本申请中提出的目的是确定哺乳动物正呼肠孤病毒（呼肠孤病毒）如何运输 从最初的接种部位到血液中。以前的研究表明，非结构性 蛋白σ1s是呼肠孤病毒通过血行途径传播所必需的。新的初步数据 表明σ1s的功能是增强呼肠孤病毒蛋白质的合成，这使得呼肠孤病毒能够 在IFN应答存在的情况下，在细胞类型中有效复制， 脉管系统总之，这些数据表明，σ 1s介导的宿主IFN应答失活 允许呼肠孤病毒克服限制进入血流的细胞屏障。基于 初步研究，具体目标1中的实验将定义传播所需的细胞类型， 呼肠孤病毒从接种部位进入血液。具体目标2中的实验将定义 σ1s促进呼肠孤病毒蛋白合成的机制。建议的实验 具体目标3将研究呼肠孤病毒血流传播如何有助于病毒清除， 中枢神经系统这些实验将使用强大的鼠标和 呼肠孤病毒遗传学系统，以解决呼肠孤病毒如何获得进入血液。这项研究将 在揭示控制系统性病毒传播的统一原则方面具有广泛的普遍影响。

PROJECT SUMMARY Viral spread from the mucosal sites of infection to target tissues and organs is a fundamental step in the pathogenesis of many viral diseases. Viruses typically use the bloodstream and lymphatic system as the pathway for delivering virus to organs and tissues throughout the body. Although general principles of lymphatic-hematogenous viral spread are understood, little is known about the viral and cellular determinants that govern virus dissemination by these routes. The overall objective of experiments described in this application is to define mechanisms and functional consequences of viral spread via the blood. Work proposed in this application seeks determine how mammalian orthoreovirus (reovirus) traffics from an initial site of inoculation to the bloodstream. Previous studies revealed that nonstructural protein σ1s is required for reovirus spread by hematogenous routes. New preliminary data indicates that σ1s functions to enhance reovirus protein synthesis, which allows reovirus to replicate efficiently in the presence of an IFN response in cell types that provide access to the vasculature. Together, these data indicate that σ1s-mediated inactivation of host IFN responses allows reovirus to overcome cellular barriers that restrict access to the bloodstream. Based on preliminary studies, experiments in Specific Aim 1 will define cell types required to disseminate reovirus from the site of inoculation to the bloodstream. Experiments in Specific Aim 2 will define mechanisms by which σ1s promotes reovirus protein synthesis. Experiments proposed in Specific Aim 3 will examine how reovirus bloodstream spread contributes to viral clearance from the central nervous system. These experiments will use a combination of powerful mouse and reovirus genetics systems to address how reovirus gains access to the blood. This research will have broad general impact in uncovering unifying principles that govern systemic viral spread.