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: 7491029
• 负责人: Christoph Seeger
• 金额: $ 37.74万
• 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/7491029
• 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; Purpose; 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）：我们对西尼罗病毒（WNV）先天免疫应答的研究，导致发现西尼罗病毒复制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，而这是在IFN作用下建立抗病毒状态所必需的。拟议的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。