Mechanisms of Reovirus Bloodstream Dissemination

项目总结 病毒从感染的粘膜部位传播到目标组织和器官是一种 在许多病毒性疾病的发病机制中的基本步骤。病毒通常使用 血液和淋巴系统是将病毒运送到器官和组织的途径 遍及全身。尽管淋巴-血源性病毒传播的一般原理是 人们对控制病毒的病毒和细胞决定因素知之甚少。 通过这些途径进行传播。此应用程序中描述的实验的总体目标 就是定义病毒通过血液传播的机制和功能后果。工作 在本申请中提出的旨在确定哺乳动物呼肠孤病毒(呼肠孤病毒)如何传播 从最初的接种部位到血液。以前的研究表明，非结构性的 呼肠孤病毒通过血液途径传播需要蛋白σ1S。新的初步数据 表明σ1S具有增强呼肠孤病毒蛋白质合成的功能，这使得呼肠孤病毒能够 在存在干扰素反应的细胞类型中进行高效复制，这些细胞类型提供访问 脉管系统。综上所述，这些数据表明σ-1s介导的宿主干扰素反应失活 允许呼肠孤病毒克服限制进入血液的细胞屏障。基于 初步研究，特定目标1的实验将确定传播所需的细胞类型 呼肠孤病毒从接种部位进入血液。在特定目标2中的实验将定义 σ-1S促进呼肠孤病毒蛋白合成的机制。建议进行的实验 特定目标3将研究呼肠孤病毒血流传播如何有助于病毒从 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，解决呼肠孤病毒如何进入血液。这项研究将 在揭示管理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.