Inhibition of the Interferon Response by West Nile Virus

西尼罗河病毒对干扰素反应的抑制

• 批准号: 7676081
• 负责人: Christoph Seeger
• 金额: $ 38.52万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676081
• 关键词: Affect; Antiviral Agents; Antiviral Therapy; Binding; Biochemical; Biochemical Genetics; Biological Assay; Cells; Cessation of life; Complex; Development; Elderly; Encephalitis; Family member; Flaviviridae; Flavivirus; Genes; Genetic; Goals; Hepatitis B; Hepatitis C virus; Human; Immune response; Immune system; Infection; Interferon Activation; Interferon-alpha; Interferons; Investigation; JAK1 gene; Janus kinase; Knowledge; Nature; Outcome; Paralysed; Pathogenesis; Phosphorylation; Play; Process; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Research; Role; Signal Transduction Pathway; Staging; Structural Protein; System; TYK2; Testing; Vaccination; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; base; design; genetic analysis; mutant; pathogen; prevent; programs; receptor; research study; response; stable cell line; virus host interaction

DESCRIPTION (provided by applicant): Our investigations of the innate immune response against West Nile virus (WNV), led to the discovery that WNV replication inhibits the signal transduction pathways used by interferons to induce cellular antiviral programs. The results indicated that one or more viral non-structural (NS) proteins inhibit the phosphorylation and activation of the Janus kinases JAK1 and Tyk2, which is required to establish an antiviral state in response to IFN. The purpose of the proposed research program is to investigate the mechanism responsible for this inhibition of the IFN response through three specific aims. In the first aim, we will use a genetic approach to identify the viral protein(s) that are responsible for the observed inhibition of the IFNa response in WNV infected cells. Our goal is to identify replication competent WNV mutants that have lost the ability to inhibit the IFN response. With a biochemical approach described in the second aim, we will investigate the host-virus interactions that play a role in the inhibition of the IFN signal transduction pathway in WNV infected cells. Specifically, we will determine if viral proteins inhibit the IFN response directly through binding to the IFNa receptor complex or if they operate indirectly by activating a cellular antagonist, such as a protein tyrosine phosphatase or other known negative regulators of the IFN response. Experiments were designed to identify the cellular factors that provide targets for the viral antagonists. With the third aim, we will investigate how the relationship between the host innate immune response and viral components influences the outcome of WNV infections. With the help of a system permitting the conditional expression of IFN-induced genes, we will investigate how cellular antiviral mechanisms inhibit WNV replication and determine the nature of the cellular genes that constitute the innate antiviral program against WNV. WNV has emerged as a pathogen of global significance that can cause paralysis, meningo-encephalitis, and death. Primary WNV infections cannot yet be prevented by vaccination and, so far, treatments to prevent the serious consequences of infections that affect particularly the elderly are not yet available. The studies proposed here will provide a better understanding of host-virus interactions that control WNV replication and pathogenesis. This new information can be used as the basis for the development of effective antiviral therapies.

描述（由申请人提供）：我们对针对西尼罗河病毒（WNV）的先天免疫反应的研究发现，WNV 复制会抑制干扰素用于诱导细胞抗病毒程序的信号转导途径。结果表明，一种或多种病毒非结构（NS）蛋白抑制 Janus 激酶 JAK1 和 Tyk2 的磷酸化和激活，这是建立响应 IFN 的抗病毒状态所必需的。拟议研究计划的目的是通过三个具体目标来研究抑制 IFN 反应的机制。 第一个目标是，我们将使用遗传方法来鉴定导致观察到的 WNV 感染细胞中 IFNa 反应抑制的病毒蛋白。我们的目标是鉴定具有复制能力的 WNV 突变体，这些突变体失去了抑制 IFN 反应的能力。通过第二个目标中描述的生化方法，我们将研究在抑制 WNV 感染细胞中的 IFN 信号转导途径中发挥作用的宿主病毒相互作用。具体来说，我们将确定病毒蛋白是否通过与 IFNα 受体复合物结合直接抑制 IFN 反应，或者它们是否通过激活细胞拮抗剂（例如蛋白酪氨酸磷酸酶或其他已知的 IFN 反应负调节剂）间接发挥作用。实验旨在确定为病毒拮抗剂提供靶点的细胞因子。第三个目标是，我们将研究宿主先天免疫反应和病毒成分之间的关​​系如何影响西尼罗河病毒感染的结果。在允许 IFN 诱导基因条件表达的系统的帮助下，我们将研究细胞抗病毒机制如何抑制 WNV 复制，并确定构成针对 WNV 的先天抗病毒程序的细胞基因的性质。 西尼罗河病毒已成为一种具有全球意义的病原体，可导致瘫痪、脑膜脑炎和死亡。原发性西尼罗河病毒感染尚不能通过疫苗接种来预防，而且迄今为止，尚无治疗方法来预防感染（特别是影响老年人）的严重后果。这里提出的研究将有助于更好地了解控制西尼罗河病毒复制和发病机制的宿主病毒相互作用。这一新信息可以作为开发有效抗病毒疗法的基础。