Innate Intracellular Response to West Nile Virus

描述（由申请人提供）：西尼罗河病毒（WNV）于1999年引入西半球，在随后的传播季节，人类疾病的发病率和严重程度急剧增加，导致其被归类为一种具有重大公共卫生问题的新兴病原体。在西尼罗河病毒流行多年的亚洲、中东和非洲地区，感染通常无症状或与轻度儿童发热性疾病有关。最近西尼罗河病毒在欧洲和美国发达国家的流行与发病率和死亡率显著升高有关，表明出现了一种致病性更强的病毒变体。自其引入美国以来，WNV已迅速传播，并且现在已在美国大陆的几乎每个州被检测到。WNV发病机制增加的分子机制目前尚不清楚，但可能包括新的病毒-宿主相互作用，其允许病毒克服或逃避宿主先天性和/或适应性免疫应答。本研究的目的是确定致病性西尼罗河病毒分离株和宿主先天性细胞内反应之间的相互作用。该提案旨在研究宿主干扰素调节因子3（IRF-3），宿主急性抗病毒反应的核心组成部分，对西尼罗河病毒复制和发病机制的影响。已经阐明了两个目标：1）定义WNV的IRF-3信号传导机制，和2）定义IRF-3途径对WNV复制的影响。更全面地了解先天性细胞内对西尼罗河病毒的反应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.