Defining the host antiviral response to West Nile Virus

描述（由申请人提供）：西尼罗河病毒（WNV）是NIAID的B类传染性病原体，自1999年传入美国以来，已成为美国虫媒病毒性脑炎的主要原因。在最近的西尼罗河病毒暴发中，健康的年轻人受到神经系统疾病发病率增加的折磨，这表明毒力可以独立于衰老或与衰老相关的免疫缺陷而发生。这表明，在美国，西尼罗河病毒的致病菌株足以调节免疫力，导致健康的年轻人患病。在这一点上，没有针对西尼罗河病毒的疫苗，治疗只是支持性的。WNV与先天免疫信号通路的相互作用尚未明确。我们实验室的研究表明，I型干扰素（IFN）在控制西尼罗河病毒复制和毒力方面至关重要。我们的实验室还发现，来自宿主细胞质病毒传感器rig - 1和MDA5的先天免疫信号在触发对西nv的先天免疫应答中至关重要。然而，它们在体内的相关性或它们在触发针对西尼罗河病毒的细胞和组织特异性抗病毒防御程序中的作用尚未明确。为了解决这些问题，本提案概述了以下目标：1)确定rig - 1和MDA-5在触发宿主先天免疫反应中针对I和II系西尼罗病毒株的作用；2)明确调控西尼罗河病毒感染的先天免疫效应基因。我们将利用基于细胞的、生化的、病毒学的和功能基因组学的方法来定义rig -1、MDA5和IPS-1接头蛋白的作用。我们将利用敲除小鼠和从这些小鼠中产生的原代细胞来评估毒力、病毒传播、细胞趋向性和发病机制，以确定西尼罗病毒感染引发的先天免疫反应。这些研究将更清楚地定义宿主免疫反应和西尼罗河病毒发病机制之间的界面，并为指导旨在调节感染免疫的治疗和疫苗策略提供新的见解。公共卫生相关性：自1999年以来，西尼罗河病毒已成为一种重大的公共卫生威胁。2007年，西尼罗河病毒造成3598例感染，症状包括脑膜炎、脑炎和发热，造成121人死亡。由于没有可用的疫苗，对感染的治疗也很少，因此必须进行研究，以更好地确定宿主抗病毒反应与西尼罗河病毒发病机制之间的界面。

DESCRIPTION (provided by applicant): West Nile Virus (WNV) is an NIAID Category B infectious agent and since its introduction into the United States in 1999, has become the leading cause of arboviral encephalitis in the United States. In recent WNV outbreaks, healthy young adults have been afflicted with increasing incidences of neurological disease demonstrating that virulence can occur independently of senescence or immune deficiencies associated with aging. This suggests that pathogenic strains of WNV in the United States modulate immunity sufficiently to cause disease in healthy young adults. At this point, there is no vaccine against WNV and treatment is only supportive. The WNV interactions with the innate immune signaling pathways are not well defined. Studies from our laboratory have demonstrated that type I interferon (IFN) is critical in controlling WNV replication and virulence. Our laboratory has also found that innate immune signaling from the host cytoplasmic viral sensors, RIG-I and MDA5, are critical in triggering an innate immune response to WNV. However, their in vivo relevance or their roles in triggering cell and tissue- specific antiviral defense programs against WNV are well not defined. To address these issues, the following objectives have been outlined in this proposal: 1) Define the roles of RIG-I and MDA-5 in triggering the host innate immune response against lineage I and lineage II West Nile virus strains; 2) Define the innate immune effector genes that regulate WNV infection. We will utilize cell-based, biochemical, virological, and a functional genomics approach to define the roles of, RIG-I, and MDA5, and the IPS-1 adaptor protein. We will utilize knockout mice and primary cells generated from these mice to evaluate virulence, viral spread, cell tropism, and pathogenesis to define the innate immune response triggered by West Nile virus infection. These studies will more clearly define the interface between the host immune response and WNV pathogenesis and provide novel insights to guide therapeutic and vaccine strategies aimed at modulating immunity to infection. PUBLIC HEALTH RELEVANCE: Since 1999, WNV has emerged as a significant public health threat. In 2007, WNV caused 3598 cases of infection with symptoms ranging from meningitis, encephalitis, and debilitating fever and caused 121 fatalities. With no vaccine available and therapy to infection being only minimal, studies have to be conducted to better define the interface between the host antiviral response and WNV pathogenesis.