Novel Nucleic Acid Sensing NLRs and Innate Immunity to Viruses

新型核酸传感 NLR 和病毒先天免疫

• 批准号: 9233910
• 负责人: Jenny P Ting
• 金额: $ 41.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233910
• 关键词: Affect; Agonist; Agreement; Alpha Cell; Attenuated; Autophagocytosis; Bacterial Infections; Binding; Biochemical; Biological Assay; CASP1 gene; Cell-Free System; Cells; Collaborations; Complex; DNA; DNA Binding; DNA Viruses; Data; Dengue; Double Stranded DNA Virus; Electron Microscopy; Family; Global Change; Goals; Hepatitis A Virus; Herpesviridae; Human; Human Cell Line; Image; Immune; Immune response; Immune signaling; Immunity; Immunology; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza; Innate Immune Response; Innate Immune System; Interferons; Interleukin-18; Investigation; Lead; Length; Leucine-Rich Repeat; Ligand Binding; Ligands; Mediating; Mitochondrial Proteins; Molecular; National Institute of Allergy and Infectious Disease; Natural Immunity; Nucleic Acid Binding; Nucleic Acids; Nucleotides; Paper; Pathway interactions; Pattern; Pattern recognition receptor; Peptidoglycan; Phosphotransferases; Production; Proteins; Proteome; Proteomics; RNA; RNA Binding; RNA Viruses; Recruitment Activity; Regulation; Reporting; Research; Role; Signal Pathway; Site; TBK1 gene; Testing; Toll-like receptors; Viral; Virus; Virus Diseases; Virus Receptors; Work; cytokine; experimental study; immune activation; member; novel; pathogen; programs; receptor; receptor binding; receptor function; response; sensor; trafficking

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.

与病原体相关的分子模式（PAMP）引人入胜的模式识别受体（PRR）启动先天免疫的概念已彻底改变了免疫学。我们首先报道了22个成员NLR（核苷酸结合和富含亮氨酸的重复或点头样受体）家族。大多数NLR都激活了先天免疫力，主要实例是NODI和N0D2，它们识别细菌肽聚糖和炎性型NLR，这些NLR会触发caspase-1激活，从而导致IL-1B和ILI8成熟。最近，我们和其他几个组记录了一个新的NLR亚家族，该家族降低了炎症和免疫激活，该家族由NLRP4，NLRP6，NLRP12，NLRC3，NLRC3，NLRC5和NLRXI组成。这些蛋白质主要通过与天生免疫系统中的衔接子和信号通路相互作用来起作用。在此提案中，我们将研究其中一些新型NLR的交集，以调节宿主对许多NIAID优先级RNA和DNA病毒的反应。我们将采用几种尖端蛋白质组学方法来评估依赖于NIAID优先病毒病原体感染期间NLR的特定蛋白质组织。这些方向与RFA确切一致，该RFA指出：“针对该FOA提出的研究的重点应该在于定义与病毒感染免疫有关的新型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许多相关病毒在优先病原体列表中。它通过（a）研究新的PRR作为病毒核酸的传感器或受体的作用来支持该程序的总体目标，这些传感器或受体会影响人类对NIAID高优先病毒病原体的随后的先天免疫反应； （b）应用尖端定量蛋白质组学方法来鉴定病原体传感的新型范式转移途径； （c）评估多个PRR之间的串扰； （d）使用独特的生化能力，在技术上具有挑战性地研究了PRR的配体结合功能，以及（e）使用原始材料进行实验。该项目将涉及与项目2和3的广泛合作以及核心A-C。