Innate Intracellular Response to West Nile Virus

描述(申请人提供)：西尼罗河病毒(西尼罗河病毒)于1999年进入西半球，在随后的传播季节，人类的发病率和严重程度都急剧上升，导致其被归类为重大公共卫生关切的新病原体。在西尼罗河病毒流行多年的亚洲、中东和非洲地区，感染一般没有症状或与轻微的儿童发热性疾病有关。最近在欧洲和美国发达国家的西尼罗河病毒流行与显著更高的发病率和死亡率有关，这表明出现了一种更具致病性的病毒变种。自传入美国以来，西尼罗河病毒迅速传播，现已在美国大陆的几乎每个州都被检测到。西尼罗河病毒致病机制目前尚不清楚，但可能包括新的病毒与宿主的相互作用，使病毒能够克服或逃避宿主的先天和/或获得性免疫反应。这项研究计划的目标是确定致病性西尼罗河病毒分离株与宿主固有的细胞内反应之间的相互作用。这项建议旨在研究宿主急性抗病毒反应的中心成分宿主干扰素调节因子3(IRF-3)对西尼罗河病毒复制和致病机制的影响。目前已经提出了两个目标：1)确定西尼罗河病毒对IRF-3信号转导的机制，2)确定IRF-3途径对西尼罗河病毒复制的影响。对西尼罗河病毒固有的细胞内反应的更全面的了解将有助于开发新的治疗方法来对抗西尼罗河病毒感染。

DESCRIPTION (provided by applicant): The introduction of West Nile virus (WNV) in to the western hemisphere in 1999 and dramatic increase in both the rate and severity of disease in humans during subsequent transmission seasons, has resulted in its classification as an emerging pathogen of significant public health concern. In areas of Asia, the Middle East and Africa where WNV has been endemic for many years, infections are generally asymptomatic or associated with a mild childhood febrile illness. Recent WNV epidemics in developed countries in Europe and the United States have been associated with significantly higher rates of morbidity and mortality, indicating the emergence of a more pathogenic variant of the virus. Since its introduction into the United States WNV has rapidly spread and has now been detected in nearly every state in the continental U.S.A. The molecular mechanisms for the increase in pathogenesis of WNV are currently unknown but are likely to include novel virus-host interactions that allow the virus to overcome or evade the host innate and/or adaptive immune response. The goal of this research proposal is to define the interactions between a pathogenic WNV isolate and the host innate intracellular response. This proposal is designed to investigate the influence of the host interferon regulatory factor 3 (IRF-3), a central component of the host acute antiviral response, on WNV replication and pathogenesis. Two objectives have been utlined; 1) define the mechanism of IRF-3 signaling by WNV, and 2) define the effect of the IRF-3 pathway upon WNV replication. A more complete understanding of the innate intracellular response to WNV will aid in the development of novel therapeutic approaches to combat WNV infections.