Discovery of New Innate Immune Pathways in Viral Recognition

描述（由申请人提供）：先天免疫的一个主要概念性进展是病原体识别受体（PRR）的发现，其深刻地塑造了适应性免疫，以影响宿主对病原体的反应。Toll样受体和RIG-I样受体是先天免疫应答的主要受体，而NLR（nucleotide-binding leucine rich repeat containing，NOD样受体）家族在病毒感染中的作用是研究最多的 才刚刚出现在该计划中，我们将重点关注与多种NIAID优先病原体相关的新型核酸传感途径的揭示。该计划由三个项目组成，每个项目由其所在领域的国际领导者领导。该计划将以高度协作的方式与两个核心进行，这两个核心将提供尖端的蛋白质组学和蛋白质纯化能力，由在PRR领域做出开创性工作的董事领导。总体目标是： * 研究新型PRRs作为病毒核酸受体在影响人类对NIAID高优先级病毒病原体的先天免疫应答中的作用。 * 应用尖端的定量蛋白质组学方法来识别病原体传感的新型范式转变途径。 * 对比和比较PRR在不同NIAID高优先级人类病毒中的作用。 * 揭示宿主对NIAID优先人类病毒应答中多种PRR之间的相互作用 * 研究病毒配体向PRR识别位点的细胞内运输。 * 利用独特的生物化学能力，在技术上具有挑战性，以量化PRR的配体结合功能。 * 最大限度地利用主要人体材料验证实验结果的机会。 这些目标是对RFA-AI-12 - 048的高度响应，并且与RFA的声明目的完全一致，即“响应本FOA提出的研究重点应是定义涉及病毒感染免疫的新型细胞和分子免疫机制”。它也是响应性的，因为探索的途径与多种高优先级病原体广泛相关，并将在五种高优先级RNA和DNA病毒的背景下进行研究。最后，拟议的工作是响应RFA的目的，因为它特别扩大了我们对新的PRR与病毒的相互作用的理解，以及通过分析NIAID优先病毒病原体引起的人类先天免疫细胞中的蛋白质组修饰而伴随的信号通路变化。

DESCRIPTION (as provided by applicant): A major conceptual advance in innate immunity is the discovery of Pathogen Recognition Receptors (PRR), which profoundly shape adaptive immunity to affect host response to pathogens. Major PRRs crucial for innate immunity against viral pathogens include toll-like receptors and RIG-I like receptors, while the role for NLR (nucleotide-binding leucine rich repeat containing, or NOD-like receptor) family in viral infection is just emerging. In this Program, we will focus on the revelation of novel nucleic acid sensing pathways relevant to multiple NIAID priority pathogens. The Program is comprised of three Projects, each led by an international leader in his/her field. The Program will be performed in a highly collaborative fashion with two Cores which will provide cutting edge proteomics and protein purification capabilities, headed by directors who have contributed seminal work in the field of PRRs. The overarching goals are: * To investigate the role of novel PRRs as receptors of viral nucleic acid which affect subsequent innate immune responses to NIAID high priority viral pathogens in human. * To apply cutting edge quantitative proteomic approaches for the identification of novel paradigm-shifting pathways of pathogen sensing. * To contrast and compare role of PRRs across diverse NIAID high priority human viruses. * To reveal cross-talk between multiple PRRs in host response to NIAID priority human viruses * To investigate intracellular trafficking of viral ligands to sites of recognition by PRRs. * To capitalize on unique biochemical capabilities that are technically challenging to quantify the ligand-binding functions of PRRs. * To maximize opportunities for validating experimental findings with primary human materials. These goals are highly response to the RFA-AI-12-048 and are in precise concordance with the stated purpose of the RFA 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". It is also responsive because the pathways explored are broadly relevant to multiple high priority pathogens and will be studied in the context of five high priority RNA and DNA viruses. Finally, the proposed work is responsive to the purpose of the RFA because it specifically expands our understanding of novel PRR interaction with viruses and the accompanied changes in signaling pathways by profiling proteomic modifications in human innate immune cells caused by NIAID priority viral pathogens.