Defining the role of the Inflammasome in immunity against Flavivirus Infection

描述(申请人提供)：西尼罗河病毒(WNV)是一种模式黄病毒和NIAID B类传染病/新兴病原体。此外，它是一种新的公共卫生威胁，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经历了一种急性发热病，但也有一小部分人进展为中枢神经系统受累和脑炎疾病。在西尼罗河病毒感染期间，已经确定了多种病毒和宿主因素，这些因素有助于疾病和保护。然而，目前仍不清楚定义西尼罗河病毒病进展为脑炎的炎症信号和病毒调节特性。炎症体是机体对感染的先天免疫反应的主要组成部分，通过激活和分泌包括IL-1β在内的一系列细胞因子，在推动免疫激活中发挥重要作用。我们的初步研究已经确定了对西尼罗河病毒感染的保护性免疫需要IL-1信号和炎症小体的成分。此外，我们还揭示了模式识别传感分子家族(RIG-I样受体，RLRs)在驱动IL-1和炎症体激活方面的潜在作用。我们未来的目标是解决西尼罗河病毒与体内和体外炎症小体之间的相互作用。具体地说，我们将(1)研究触发IL-1的宿主免疫信号通路，(2)检测作为炎症小体激活激动剂的病毒因子，(3)确定炎小体和IL-1信号在保护性免疫中的作用机制，以及WNV对中枢神经系统脑炎疾病的限制。总之，这些研究将使我们能够更好地了解对黄病毒感染的免疫中炎症信号的要求，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，从而对黄病毒疾病采取治疗和预防行动。 公共卫生相关性：西尼罗河病毒(WNV)是美国蚊媒脑炎的主要原因之一。此外，西尼罗河病毒及其相关属成员，包括登革热病毒，在美国和全球都是新出现的公共卫生威胁。目前，还没有治疗或预防由西尼罗河病毒介导的疾病的治疗或疫苗策略，因此开发这些工具是必要的。了解黄病毒与炎症小体等免疫信号通路之间的相互作用，将有助于了解保护性免疫所需的宿主和病毒因子，并导致针对西尼罗河病毒和其他相关黄病毒的新疗法和预防性疫苗的开发。

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. PUBLIC HEALTH RELEVANCE: West Nile Virus (WNV) is one of the leading causes of mosquito-borne encephalitis in the United States. In addition, WNV and its related genus members, including Dengue Virus, are emerging public health threats both in the U.S. and globally. Currently, there are no therapeutics or vaccine strategies for treating or preventing disease mediated by WNV making the development of these tools necessary. Understanding the interactions between flaviviruses and immune signaling pathways like the inflammasome will shed new light into host and viral factors required for protective immunity and lead to the development of novel therapeutics and preventative vaccines against WNV and other related flaviviruses.