Innate Immunity in Pneumonic Sepsis

肺炎败血症的先天免疫

基本信息

批准号：
9383252
负责人：
Shanshan Cai
金额：
$ 37万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9383252
关键词：
Adaptor Signaling Protein Address Adoptive Transfer Anti-Bacterial Agents Anti-Inflammatory Agents Antibiotic Therapy Attenuated Bacteria Bacterial Drug Resistance Bacterial Infections Bacterial Pneumonia Binding CASP1 gene Cells Clinical Coculture Techniques Death Rate Defense Mechanisms Dendritic Cells Disease Equilibrium Goals Health Expenditures Host Defense Host Defense Mechanism Host resistance Human Immune Immune signaling Immunity Immunotherapeutic agent Immunotherapy In Vitro Infection Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Interleukin-1 Interleukin-17 Interleukin-18 Interleukins Investigation Klebsiella pneumonia bacterium Knockout Mice Lung Lymphocyte Mediating Morbidity - disease rate Multi-Drug Resistance Mus Myeloid Cells Natural Immunity Neutrophil Infiltration Nucleotides Organ Pathway interactions Pneumonia Population Prevention strategy Production RIPK2 gene Resistance Role Sepsis Signal Transduction System Systemic infection T-Lymphocyte Testing Tissues Toll-like receptors Vaccines Variant Work burden of illness carbapenemase chemokine cytokine design extracellular improved in vivo innovation interleukin-23 migration mortality neutrophil novel overexpression pathogen receptor response treatment strategy

项目摘要

SUMMARY Lung infections are a leading cause of sepsis that poses global mortality and morbidity. Effective clearance of pathogens from the lung is dependent on successful innate immunity. Understanding the innate defense mechanisms in the lung is crucial for improved immunotherapeutics or vaccines to reduce this burden of disease. The signaling cascades triggering innate immunity consist of a delicate balance between pro-inflammatory responses, and counteracting anti-inflammatory responses. It is however poorly understood how these innate immune signaling cascades converge to provide efficient host defense while attenuating inflammatory tissue damage. To delineate the host defense mechanisms in the lungs and extrapulmonary organs, we have focused on a primary gram-negative extracellular pathogen, Klebsiella pneumoniae since this bacterium induces severe pneumonia followed by sepsis; and multiple drug-resistant and hypervirulent variants have recently emerged to cause devastating pulmonary and systemic infections. Recognition of pathogens is the first critical step leading to neutrophil influx in the lung. Regarding bacterial recognition, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) were implicated. However, the role of NLRs, such as NOD1 and NOD2 s in host defense against K. pneumoniae remains unexplored. NOD1/2 signaling cascades involve the adaptor protein RIP2. We now provide preliminary evidence that NOD2 is involved in host defense during K. pneumoniae infection, which include: 1) Mice deficient in RIP2 demonstrate reduced survival, higher bacterial burden and decreased neutrophil recruitment to the lungs and extrapulmonary organs; 2) NOD2-deficient mice show attenuated neutrophil recruitment to the lungs; 3) NOD2-deficient mice demonstrate decreased caspase- 1 activation and interleukin (IL)-1productionin the lung; 4) Both IL-1 and IL-18 are important for host resistance against K. pneumoniae and 5) RIP2 regulates IL-23 and IL-17 production in the lungs. These findings collectively support the hypothesis that the initial interaction of K. pneumoniae with the lung cells leads to NOD2 activation followed by IL-1and IL-18 production which then induces IL-17A- mediated neutrophil-dependent immunity in the host. The Aims are: (1) Investigate the in vivo mechanisms by which NOD2 modulates neutrophil-mediated host defense during pneumonic sepsis; (2) Explore the in vivo mechanisms by which NOD2 enhances IL-17A production during pneumonic sepsis; and (3) Determine if modulation of NOD2 alters host defense during pneumonic sepsis. A unique combination of in vivo and in vitro systems, including KO mice, overexpression and adoptive transfer strategies will be employed to address these aims. We believe that this conceptually, technically and translationally innovative proposal will reveal NOD2 as a master regulator for pneumonic sepsis and advance our understanding of how NOD2 promotes a beneficial response for pneumonic sepsis.

概括肺部感染是导致全球死亡率和发病率的败血症的主要原因。从肺部清除病原体取决于成功的先天免疫。肺部的先天防御机制对于改进免疫疗法或疫苗以减少触发先天免疫的信号级联由微妙的平衡组成。促炎症反应和抵消抗炎症反应之间的关系。人们对这些先天免疫信号级联如何汇聚以提供有效的宿主知之甚少防御，同时减轻炎症组织损伤。描述宿主的防御机制。肺和肺外器官，我们重点关注一种主要的革兰氏阴性细胞外病原体，肺炎克雷伯菌，因为这种细菌会诱发严重肺炎，然后引发败血症和多发性肺炎；最近出现了耐药性和高毒力变种，可导致毁灭性的肺部和识别病原体是导致全身中性粒细胞流入的第一个关键步骤。关于细菌识别，核苷酸结合寡聚结构域（NOD）样受体 (NLR) 然而，NLR（例如 NOD1 和 NOD2）在宿主防御中的作用。肺炎克雷伯菌的 NOD1/2 信号级联涉及接头蛋白 RIP2。现在提供初步证据表明NOD2在肺炎克雷伯菌感染期间参与宿主防御，其中包括：1) RIP2 缺陷的小鼠表现出存活率降低、细菌负荷增加以及 2) NOD2缺陷小鼠表现 3) NOD2缺陷小鼠表现出半胱天冬酶减少- 1 肺中白细胞介素 (IL)-1 的激活和产生；4) IL-1 和 IL-18 对宿主都很重要 5) RIP2 调节肺部 IL-23 和 IL-17 的产生。研究结果共同支持了以下假设：肺炎克雷伯菌最初与肺部相互作用细胞导致 NOD2 激活，然后产生 IL-1和 IL-18，然后诱导 IL-17A- 宿主中介导的中性粒细胞依赖性免疫的目的是：（1）研究体内的免疫。 NOD2 在肺炎败血症期间调节中性粒细胞介导的宿主防御的机制 (2) 探索NOD2在肺炎败血症期间增强IL-17A产生的体内机制； (3) 确定 NOD2 的调节是否会改变肺炎败血症期间的宿主防御。体内和体外系统的结合，包括KO小鼠、过表达和过继转移我们认为，这将在概念上、技术上和技术上实现这些目标。转化创新提案将揭示 NOD2 作为肺炎败血症的主要调节因子加深我们对 NOD2 如何促进肺炎败血症的有益反应的理解。