West Nile virus interactions with the innate antiviral response

描述（由申请人提供）：最近在欧洲、以色列和美国的未感染人群中引入了西尼罗河病毒（WNV）的高致病性毒株，导致了流行病，与以前的爆发相比，报告病例数和疾病严重程度均显著增加。最近出现的西尼罗河病毒株的毒性增加，由于抗病毒疗法和疫苗目前还不能用于人类，这一事实进一步复杂化。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，使病毒克服或逃避宿主的先天性和/或适应性免疫反应。我们的初步研究表明，致病性和非致病性菌株的西尼罗河病毒显着不同的相互作用与先天的抗病毒程序。这表明，对致病性和非致病性西尼罗河病毒株的抗病毒反应的比较将提供关键的见解，在病毒因素参与西尼罗河病毒介导的发病机制。本提案的具体目的是（1）确定参与检测WNV致病性和非致病性菌株的模式识别受体（2）鉴定WNV感染期间产生的先天性抗病毒反应的激动剂和（3）确定负责WNV毒力的病毒因子。更好地了解不同毒力表型的菌株如何与先天性抗病毒反应相互作用，将有助于开发有效的疫苗和治疗剂。公共卫生相关性：细胞检测和应对入侵病原体的能力对于其抵御感染的能力至关重要。该提案将研究细胞如何检测西尼罗河病毒感染，以及病毒利用来控制细胞环境的机制。

DESCRIPTION (provided by applicant): The recent introduction of a highly pathogenic strains of West Nile Virus (WNV) into naive populations in Europe, Israel and the United States have resulted in epidemics with a marked increase in both the number of reported cases and the severity of disease compared to previous outbreaks. The increased virulence of the recently emerged strain of WNV is further complicated by the fact that antiviral therapies and vaccines are not currently available for use in humans. The molecular mechanisms for the increase in pathogenesis of WNV are currently unknown but are likely to include novel viral-host interactions that allow the virus to overcome or evade the host innate and/or adaptive immune response. Our preliminary studies indicate that pathogenic and nonpathogenic strains of WNV differ dramatically in their interactions with innate antiviral programs. This suggests that the comparison of the antiviral responses to pathogenic and nonpathogenic strains of WNV will provide key insights in viral factors involved in WNV- mediated pathogenesis. The specific aim of this proposal are (1) Determination of the pattern recognition receptors involved in detecting pathogenic and nonpathogenic strains of WNV (2) Identification of agonists of the innate antiviral response generated during WNV infection and (3) Determination of viral factors responsible for WNV virulence. A greater understanding of how strains with difference virulence phenotypes interact with the innate antiviral response will aid in the development of effective vaccines and therapeutic agents. PUBLIC HEALTH RELEVANCE: The ability of the cell to detect and respond to an invading pathogen is critical to its ability to defend itself against infections. This proposal will examine how cells detect West Nile virus infections and conversely the mechanisms the virus utilizes to control the cellular environment.