Novel Nucleic Acid Sensing NLRs and Innate Immunity to Viruses

病原体相关分子模式（Pathogen-Associated Molecular Pattern, PAMPs）结合模式识别受体（Pattern Recognition Receptors， PRR）启动先天免疫的概念已经彻底改变了免疫学。我们首次报道了包含22个成员的NLR（核苷酸结合和富亮氨酸重复或nod样受体）家族。大多数nlr激活先天免疫，主要的例子是NODI和nod2，它们识别细菌肽聚糖和炎性体nlr，它们触发caspase-1激活，导致IL-1B和il - 8成熟。最近，我们和其他几个研究小组发现了一个新的NLR亚家族，它由NLRP4、NLRP6、NLRP12、NLRC3、NLRC5和NLRXI组成，可以减少炎症和免疫激活。这些蛋白主要通过与先天免疫系统中的适配器和信号通路相互作用而起作用。在本提案中，我们将研究一些新的nlr在调节宿主对一些NIAID优先RNA和DNA病毒的反应中的交集。我们将应用几种尖端的蛋白质组学方法来评估NIAID优先病毒病原体感染期间依赖NLRs的特定蛋白质组。这些方向与《区域自由协定》完全一致，其中指出，“为响应本《区域自由协定》而提出的研究重点应放在确定与病毒感染免疫有关的新的细胞和分子免疫机制”。此外，这些nlr调节宿主反应的机制广泛适用于优先病原体列表上的许多相关病毒。它通过(a)研究新型PRRs作为病毒核酸传感器或受体的作用，从而影响人类对NIAID高优先级病毒病原体的后续先天免疫反应，从而支持该计划的总体目标；(b)应用尖端的定量蛋白质组学方法来鉴定病原体感知的新范式转移途径；(c)评估多个PRRs之间的串扰；(d)利用在技术上具有挑战性的独特生化能力来研究PRRs的配体结合功能，以及(e)用原始人体材料进行实验。该项目将涉及与项目2和项目3以及核心A-C的广泛合作。

The concept of Pathogen-Associated Molecular Pattern (PAMPs) engaging Pattern Recognition Receptors (PRR) to initiate innate immunity has revolutionized immunology. We first reported the 22- member NLR (Nucleotide-binding and Leucine Rich repeat or NOD-like receptors) family. Most NLRs activate innate immunity, prime examples being NODI and N0D2 which recognize bacterial peptidoglycan and inflammasome NLRs that trigger caspase-1 activation leading to IL-1B and ILI8 maturation. Recently, we and several other groups documented a new NLR subfamily that reduces inflammatory and immune activation which is comprised of NLRP4, NLRP6, NLRP12, NLRC3, NLRC5 and NLRXI. These proteins largely operate by interacting with adaptors and signaling pathways in the innate immune system. In this proposal we will examine the intersection of some of these novel NLRs in regulating host response to a number of NIAID Priority RNA and DNA viruses. We will apply several cutting edge proteomic approaches to assess specific proteomes that are dependent on NLRs during infection with NIAID Priority viral pathogens. These directions are in precise concordance with the RFA which states that "emphasis of research proposed in response to this FOA should be in defining novel cellular and molecular immune mechanisms involved in immunity to virus infection". Additionally, the mechanisms by which these NLRs regulate host response are broadly applicable to many viruses of relevance on the Priority Pathogens' list. It supports the overall goal of the Program by (a) investigating the role of novel PRRs as sensors or receptors of viral nucleic acid which affect subsequent innate immune responses to NIAID high priority viral pathogens in human; (b) applying cutting edge quantitative proteomic approaches for the identification of novel paradigm-shifting pathways of pathogen sensing; (c) assessing cross-talk between multiple PRRs; (d) using unique biochemical capabilities that are technically challenging to study the ligand-binding functions of PRRs, and (e) performing experiments with primary human materials. This project will involve extensive collaboration with Projects 2 and 3, as well as Cores A-C.