Innate Intracellular Response to West Nile Virus

描述（由申请人提供）：西尼罗病毒（WNV）于1999年传入西半球，在随后的传播季节中，人类疾病的发病率和严重程度急剧增加，导致其被归类为引起重大公共卫生关注的新发病原体。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。最近在欧洲和美国发达国家发生的西尼罗河病毒流行与发病率和死亡率显著升高有关，这表明出现了一种致病性更高的病毒变体。自从西尼罗河病毒传入美国以来，它迅速传播，现在几乎在美国大陆的每个州都发现了西尼罗河病毒。西尼罗河病毒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，使病毒能够克服或逃避宿主先天和/或适应性免疫反应。本研究计划的目标是确定致病性西尼罗河病毒分离物与宿主先天细胞内反应之间的相互作用。本研究旨在研究宿主干扰素调节因子3 （IRF-3）对西尼罗河病毒复制和发病机制的影响，IRF-3是宿主急性抗病毒反应的核心成分。概述了两个目标；1)明确WNV通过IRF-3信号传导的机制；2)明确IRF-3通路对WNV复制的影响。更全面地了解西尼罗河病毒对细胞内的先天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.