A critical role of NLRP6 in West Nile virus pathogenesis in mice

描述（由申请人提供）：西尼罗病毒（WNV）是美国病毒性脑炎的最重要原因，自1999年以来造成1400多例致命的人类脑膜脑炎病例。解决关于宿主-西尼罗河病毒相互作用的基本问题是开发疫苗和治疗方法的一个综合和不可或缺的部分。本项目将研究NLRP6在控制小鼠西尼罗河病毒发病机制中的关键作用，NLRP6是NOD（核苷酸结合寡聚化结构域）样受体（NLR）家族的一个不太清楚的成员。NLRP6最近被证明在化学诱导的结肠炎和结肠炎诱导的肿瘤发生中发挥保护作用，并通过阻止炎症诱导的细菌在结肠中定植来维持肠道微生物群的稳态。最近，NLRP6被证明在细菌感染期间负调控NF-kB信号。然而，我们的研究结果表明，NLRP6通过增强I型IFN应答，帮助哺乳动物宿主对抗西尼罗河病毒感染，降低西尼罗河病毒的致死率。本项目将继续研究NLRP6在体内西尼罗河病毒感染中的生理功能，并通过生化、分子和遗传等途径阐明其潜在机制。

DESCRIPTION (provided by applicant): West Nile virus (WNV) is the most significant cause of viral encephalitis in the USA, responsible for over 1400 lethal human meningoencephalitis cases since 1999. Addressing the fundamental questions regarding host-WNV interactions is an integrated and indispensable part of the effort towards development of vaccines and therapeutics. This project will investigate the critical role of NLRP6, a poorly characterized member of the NOD (nucleotide- binding oligomerization domain) like receptor (NLR) family, in controlling WNV pathogenesis in mice. NLRP6 has been recently demonstrated to play a protective role in development of chemically induced colitis as well as colitis-induced tumorigenesis, and to maintain the gut microbiome homeostasis by preventing inflammation-inducing bacteria from colonizing the colon. More recently, NLRP6 was shown to negatively regulate NF-kB signaling during bacterial infection. However, our results show that NLRP6 helps mammalian hosts fight against WNV infection and reduce WNV lethality by enhancing type I IFN response. This project will continue investigating the physiological functions of NLRP6 in WNV infection in vivo, and elucidate the underlying mechanisms through biochemical, molecular and genetic approaches.