Defining the host antiviral response to West Nile Virus

定义宿主对西尼罗河病毒的抗病毒反应

• 批准号: 7980162
• 负责人: Mehul Shamal Suthar
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980162
• 关键词: Adaptor Signaling Protein; Address; Aging; Antiviral Agents; Antiviral Response; Biochemical; Biochemical Genetics; Categories; Cell Culture Techniques; Cells; Disease; Disease Outbreaks; Encephalitis; Family member; Fever; Gene Family; Genes; Immune; Immune response; Immunity; In Vitro; Incidence; Infection; Infectious Agent; Interferon Type I; Knockout Mice; Laboratories; Mediating; Meningitis; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Pathogenesis; Public Health; Role; Signal Pathway; Signal Transduction; Symptoms; Tissues; Tropism; United States; Vaccines; Viral; Virulence; Virus Diseases; Virus Replication; West Nile virus; base; functional genomics; in vivo; insight; nervous system disorder; novel; programs; public health relevance; senescence; sensor; therapeutic vaccine; virus pathogenesis; young adult

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.

描述（由申请人提供）：西尼罗病毒 (WNV) 是一种 NIAID B 类传染原，自 1999 年引入美国以来，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爆发中，健康的年轻人遭受神经系统疾病发病率上升的困扰，这表明毒力的发生可以独立于衰老或与衰老相关的免疫缺陷。这表明美国的西尼罗河病毒致病株足以调节免疫力，导致健康年轻人患病。目前，还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) 对于控制西尼罗河病毒复制和毒力至关重要。我们的实验室还发现，来自宿主细胞质病毒传感器 RIG-I 和 MDA5 的先天免疫信号传导对于触发针对 WNV 的先天免疫反应至关重要。然而，它们的体内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不清楚。为了解决这些问题，本提案概述了以下目标： 1) 明确 RIG-I 和 MDA-5 在触发宿主针对 I 系和 II 系西尼罗病毒株的先天免疫反应中的作用； 2) 定义调节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、病毒学和功能基因组学方法来定义 RIG-I、MDA5 和 IPS-1 接头蛋白的作用。我们将利用基因敲除小鼠和这些小鼠产生的原代细胞来评估毒力、病毒传播、细胞向性和发病机制，以确定西尼罗河病毒感染引发的先天免疫反应。这些研究将更清楚地界定宿主免疫反应与西尼罗河病毒发病机制之间的联系，并为指导旨在调节感染免疫力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重大的公共卫生威胁。 2007年，西尼罗河病毒造成3598例感染病例，症状包括脑膜炎、脑炎和低烧等，并造成121人死亡。由于没有可用的疫苗，而且对感染的治疗也很有限，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联系。