Inhibition of the Interferon Response by West Nile Virus

描述（由申请人提供）：我们对西尼罗河病毒（WNV）的先天免疫应答的研究发现，WNV复制抑制干扰素诱导细胞抗病毒程序所用的信号转导途径。结果表明，一种或多种病毒非结构（NS）蛋白抑制Janus激酶JAK 1和Tyk 2的磷酸化和活化，这是响应IFN建立抗病毒状态所需的。拟议的研究计划的目的是通过三个具体目标调查负责这种抑制IFN反应的机制。 在第一个目标中，我们将使用遗传方法来鉴定负责在WNV感染的细胞中观察到的IFNa应答抑制的病毒蛋白。我们的目标是确定复制能力的WNV突变体已经失去了抑制IFN反应的能力。与第二个目标中描述的生物化学方法，我们将研究宿主-病毒的相互作用，发挥作用，在西尼罗河病毒感染的细胞中的IFN信号转导通路的抑制。具体而言，我们将确定病毒蛋白是否通过与IFNa受体复合物结合直接抑制IFN应答，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IFN应答的其他已知负调节剂）间接起作用。设计实验以鉴定为病毒拮抗剂提供靶标的细胞因子。第三个目标，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诱导基因的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全球性的病原体，可导致瘫痪、脑膜脑炎和死亡。西尼罗河病毒的主要感染尚不能通过接种疫苗来预防，到目前为止，还没有治疗方法来预防感染的严重后果，特别是影响老年人的感染。这里提出的研究将提供一个更好的理解宿主病毒的相互作用，控制西尼罗河病毒的复制和发病机制。这些新的信息可以作为开发有效的抗病毒疗法的基础。

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.