Discovery of New Innate Immune Pathways in Viral Recognition

描述(申请人提供)：先天免疫的一个主要概念进展是病原体识别受体(PRR)的发现，它深刻地塑造了适应性免疫，影响宿主对病原体的反应。对病毒病原体的天然免疫至关重要的主要PRR包括Toll样受体和Rig-I样受体，而NLR(核苷酸结合亮氨酸富含重复序列，或nod样受体)家族在病毒感染中的作用 才刚刚出现。在这一计划中，我们将重点揭示与多种NIAID优先病原体相关的新的核酸传感途径。该方案由三个项目组成，每个项目由其所在领域的一名国际领导人领导。该计划将以高度合作的方式进行，有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。首要目标是： *研究新型PRRs作为病毒核酸受体的作用，病毒核酸受体影响人类对NIAID高优先级病毒病原体随后的先天免疫反应。 *应用尖端的定量蛋白质组学方法识别病原体感知的新范式转换途径。 *对比和比较PRR在不同的NIAID高优先级人类病毒中的作用。 *揭示宿主对NIAID优先人类病毒的反应中多个PRR之间的串扰 *调查病毒配体在细胞内向PRRs识别部位的贩运。 *利用独特的生化能力，这些能力在量化PRRs的配体结合功能方面具有技术挑战性。 *最大限度地利用主要的人体材料来验证实验结果。 这些目标是对RFA-AI-12-048的高度响应，并与RFA声明的目的精确一致，即“针对该FOA提出的研究重点应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”。它还具有响应性，因为所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，拟议的工作响应了RFA的目的，因为它通过描绘由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，特别扩展了我们对新的PRR与病毒的相互作用以及伴随的信号通路变化的理解。

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.