Defining the role of the Inflammasome in immunity against Flavivirus Infection

描述（由申请方提供）：西尼罗河病毒（WNV）是黄病毒模型，是NIAID B类传染性/新发病原体。此外，它是一种新兴的公共卫生威胁，也是美国蚊媒脑炎的主要原因之一。虽然大多数感染西尼罗河病毒的人会出现急性发热性疾病，但也有一小部分人会发展为中枢神经系统受累和脑炎。已经确定了多种病毒和宿主因素，这些因素有助于疾病和西尼罗河病毒感染期间的保护。然而，目前还不清楚炎症信号和病毒调节特性，定义了一些个体的西尼罗河病毒疾病进展为脑炎。炎性小体是对感染的先天免疫应答的主要组分，并通过激活和分泌包括IL-1？在内的细胞因子家族在驱动免疫激活中发挥关键作用。我们的初步研究已经确定了对WNV感染的保护性免疫中对IL-1信号传导和炎性体组分的要求。此外，我们已经揭示了传感分子的模式识别家族（RIG-I样受体，RLR）在驱动IL-1和炎性小体的活化中的潜在作用。我们未来的目标是解决WNV和体内和离体炎性小体之间的相互作用。具体而言，我们将（1）检查参与触发IL-1？的宿主免疫信号传导途径，(2)检测作为炎性小体激活的激动剂的病毒因子和（3）确定炎性小体和IL-1信号传导有助于保护性免疫和限制由WNV引起的CNS脑炎疾病的机制。总之，这些研究将使我们能够更好地了解对黄病毒感染免疫的炎症信号传导的要求，并将进一步提高我们修改这些途径或参与这些反应的病毒因子的能力，以针对黄病毒疾病采取治疗和预防措施。

DESCRIPTION (provided by applicant): West Nile Virus (WNV) is as model flavivirus and an NIAID Category B infectious/emerging agent. In addition, it is an emerging public health threat and one of the leading causes of mosquito-borne encephalitis in the United States. While the majority of people infected with WNV experience an acute febrile disease a small percentage of individuals progress to CNS involvement and encephalitic disease. Multiple viral and host factors have been identified which contribute to disease and protection during WNV infection. However, it is still unclear as to the inflammatory signals and viral modulatory properties that define the progression of WNV disease to encephalitis in some individuals. Inflammasomes are a major component of the innate immune response to infection and play a critical role in driving immune activation through the activation and secretion of a family of cytokines including IL-1?. Our preliminary studies have identified a requirement for IL-1 signaling and components of the inflammasome in protective immunity against WNV infection. In addition, we have revealed a potential role for the pattern recognition family of sensing molecules (RIG-I-like receptors, RLRs) in driving the activation of IL-1 and inflammasomes. Our goals going forward are to address the interactions between WNV and the inflammasome in vivo and ex vivo. Specifically we will (1) examine the host immune signaling pathways involved in triggering IL-1?, (2) examine the viral factors which act as agonist for inflammasome activation and (3) determine the mechanism by which inflammasome and IL-1 signaling contribute to protective immunity and limit of CNS encephalitic disease by WNV. Together, these studies will allow us to better understand the requirements for inflammatory signaling in immunity to flavivirus infection and will further our ability to modify these pathways or viral factors involved in these responses for therapeutic and preventative action against flavivirus disease.