Novel Nucleic Acid Sensing NLRs and Innate Immunity to Viruses

病原体相关分子模式(PAMPs)参与模式识别受体(PRR)启动天然免疫的概念使免疫学发生了革命性的变化。我们首次报道了由22个成员组成的NLR(核苷酸结合和富含亮氨酸的重复或类NOD受体)家族。大多数NLR激活先天免疫，最主要的例子是NOD1和N0D2，它们识别细菌肽聚糖和炎症体NLRs，触发caspase-1激活，导致IL-1B和ILI8成熟。最近，我们和其他几个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。这些蛋白质主要通过与先天免疫系统中的接头和信号通路相互作用来发挥作用。在这项建议中，我们将研究一些新的NLRs在调节宿主对一些NIAID优先RNA和DNA病毒的反应方面的交集。我们将应用几种先进的蛋白质组学方法来评估在感染NIAID优先病毒病原体期间依赖于NLRs的特定蛋白质组。这些方向与RFA完全一致，RFA指出，“针对这种FOA提出的研究重点应该是确定涉及对病毒感染的免疫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名单上的许多相关病毒。它通过以下方式支持该计划的总体目标：(A)调查新型PRRs作为病毒核酸传感器或受体的作用，这些传感器或受体影响人类对NIAID高优先级病毒病原体的后续天然免疫反应；(B)应用尖端定量蛋白质组学方法确定病原体感应的新范式转换途径；(C)评估多个PRRs之间的相互作用；(D)使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)使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.