Initiation and regulation of antibacterial innate immunity

抗菌先天免疫的启动和调节

• 批准号: 8848342
• 负责人: Joan C Mecsas
• 金额: $ 46.74万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848342
• 关键词: Affect; Affinity; Anti-Bacterial Agents; Antigen Receptors; Atherosclerosis; Attenuated; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Bone Marrow; Cells; Complement; Coupled; Cytoplasmic Granules; Data; Diabetes Mellitus; Disease; Effectiveness; Event; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Growth; Health; Host Defense; ITAM; Immune; Immune System Diseases; Immune system; Immunity; Infection; Integrins; Knowledge; LCP2 gene; Lead; Ligands; Lupus; Mediating; Methods; Molecular; Mouse Strains; Movement; Mus; Natural Immunity; Outcome; Pathology; Pathway interactions; Phagocytosis; Phosphorylation; Play; Protein Tyrosine Phosphatase; Protein-Serine-Threonine Kinases; Proteins; Reactive Oxygen Species; Receptor Signaling; Recruitment Activity; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Site; Spleen; Syndrome; System; T-Lymphocyte; Testing; Thrombus; Tissues; Virulence; Virulence Factors; Work; Yersinia; Yersinia yopH protein; antimicrobial; bactericide; base; cell injury; cell type; cytokine; extracellular; insight; killings; mutant; neutrophil; novel; paralogous gene; pathogen; receptor; receptor coupling; response

DESCRIPTION (provided by applicant): Neutrophils (PMNs) are powerful anti-microbial cells that are rapidly mobilized and recruited to infected tissues and sites of tissue damage. Once within tissues, PMNs can deploy many activities to remove pathogens and/or damaged cells. Dysregulation of these events can have severe consequences for the host and contribute to the pathology a variety of diseases, including diabetes, thrombus formation and lupus. It has been increasingly recognized that immune cells generate appropriate responses by integrating a variety signals from receptors through multi-protein platforms, called microclusters. This signal integration has been studied extensively in T cells, but the specific rules of integration and cellular outcomes for one cell type do not necessarily apply to other cells because each cell type plays distinct roles in immunity. How PMNs integrate signals from the host and bacteria to generate the correct response in infected tissues is very poorly understood. This application seeks to uncover and understand critical molecular mechanisms PMNs employ to trigger bactericidal responses, using the bacterial pathogen, Yersinia, and its effector proteins, YopH and YopO. Based on our preliminary data indicating that YopH disrupts integration of signals by inactivating SKAP-2, PRAM-1 and SLP- 76-regulated pathways that emanate from micro-clusters, we will focus on understanding the role of SKAP2 in PMN responses. Our central hypothesis is that YopH and YopO impair PMN responses to bacteria by modulating a SKAP2-dependent system that coordinates the anti-microbial functions of PMNs triggered a variety of different types of receptors. Our aims are (1) to determine the critical functions of YopH in tissu infection; (2) dissect the role of SKAP2 in the anti-microbial responses of PMNs; and (3) understand the effects of YopO on neutrophil signaling after receptor stimulation. Through the proposed research, we expect to contribute a better understanding of the molecular mechanisms critical for PMNs anti-microbial responses. An understanding of how PMNs are inactivated by Yops in infected tissues will reveal the mechanisms by which PMNs deploy their anti-microbial and tissue damaging arsenal and lead to new ways to stop this deployment in auto-immune syndromes.

描述（由申请人提供）：中性粒细胞（PMN）是强大的抗微生物细胞，可以快速动员并募集到受感染的组织和组织损伤部位。一旦进入组织，中性粒细胞就可以发挥许多作用来清除病原体和/或受损细胞。这些事件的失调会对宿主产生严重后果，并导致多种疾病的病理学，包括糖尿病、血栓形成和狼疮。人们越来越认识到，免疫细胞通过多蛋白平台（称为微簇）整合来自受体的各种信号来产生适当的反应。这种信号整合已在 T 细胞中得到广泛研究，但一种细胞类型的整合特定规则和细胞结果不一定适用于其他细胞，因为每种细胞类型在免疫中发挥着不同的作用。人们对中性粒细胞如何整合来自宿主和细菌的信号以在受感染组织中产生正确的反应知之甚少。该应用旨在利用细菌病原体耶尔森氏菌及其效应蛋白 YopH 和 YopO 来揭示和理解 PMN 用于触发杀菌反应的关键分子机制。我们的初步数据表明 YopH 通过失活微簇发出的 SKAP-2、PRAM-1 和 SLP-76 调节途径来破坏信号整合，我们将重点了解 SKAP2 在 PMN 反应中的作用。我们的中心假设是 YopH 和 YopO 通过调节 SKAP2 依赖性系统来损害 PMN 对细菌的反应，该系统协调 PMN 的抗微生物功能，触发各种不同类型的受体。我们的目标是 (1) 确定 YopH 在组织感染中的关键功能； (2)剖析SKAP2在PMNs抗微生物反应中的作用； (3) 了解 YopO 对受体刺激后中性粒细胞信号传导的影响。通过拟议的研究，我们希望能够更好地理解中性粒细胞抗微生物反应的关键分子机制。了解 PMN 如何在受感染组织中被 Yops 灭活，将揭示 PMN 部署其抗菌和组织损伤库的机制，并找到在自身免疫综合征中阻止这种部署的新方法。