Innate Immunity in Lung Infection-induced Sepsis

肺部感染引起的脓毒症的先天免疫

• 批准号: 10626167
• 负责人: Samithamby Jeyaseelan
• 金额: $ 58.55万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626167
• 关键词: Adoptive Transfer; Adult; Alveolar Macrophages; Anti-Inflammatory Agents; Antibiotics; Attenuated; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; CASP1 gene; Cause of Death; Cells; Child; Data; Development; Epithelial Cells; Equilibrium; Family; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Health Care Costs; Host Defense; Host resistance; Human; IL17 gene; IL18 gene; IL1R1 gene; Immune; Immunotherapeutic agent; In Vitro; Infection; Inflammasome; Inflammatory; Innate Immune Response; Innate Immune System; Interleukin-1 beta; Klebsiella pneumoniae; Knock-out; Knockout Mice; Lower Respiratory Tract Infection; Lung; Lung infections; Macrophage; Membrane; Morbidity - disease rate; Multi-Drug Resistance; Mus; Myeloid Cells; Natural Immunity; Neutrophil Infiltration; Organ; Pathologic; Pathway interactions; Physiological; Pneumonia; Population; Predisposition; Prevention; Production; Public Health; Recombinants; Resistance; Respiratory System; Role; Sepsis; Septicemia; Signal Transduction; Small Interfering RNA; System; Testing; Tissues; Toll-like receptors; Vaccines; bacterial resistance; cell type; cytokine; extracellular; improved; in vivo; innate immune mechanisms; innate immune pathways; knock-down; lung injury; marenostrin; mortality; neutrophil; new therapeutic target; overexpression; pathogen; pathogenic bacteria; receptor; recruit; resistant strain; respiratory pathogen; response

SUMMARY Pulmonary infections are a leading cause of sepsis/septicemia that poses substantial mortality and long- term morbidity and health care costs. Successful clearance of pathogens from the respiratory tract is dependent on effective innate immune responses. Understanding the innate immune mechanisms in the pulmonary system is critical for better immunotherapeutics or vaccines. The signaling cascades triggering innate immune responses consist of a delicate balance between pro-inflammatory signaling cascades, and counteracting anti-inflammatory signaling. However, it is not quite clear how these innate immune cascades converge to augment clear pathogens while reducing tissue damage. To explore the host defense cascades, we have focused on a primary gram-negative extracellular pathogen, Klebsiella pneumoniae since this bacterium induces severe lung infection followed by sepsis; multiple drug-resistant strains have recently emerged; and no effective vaccine is available. The proposal will use 4 specific aims to test the overall hypothesis: NLRP10 is a critical regulator of a host defense pathway through IL-17A that can be targeted for prevention or treatment. The first aim will explore if activation of NLRP10 augments bacterial clearance and neutrophil recruitment and function. The second aim will study if the NLRP10-dependent IL-17 production enhances host defense. The third aim will examine if NLRP10 disruption causes functional alterations in alveolar macrophages. The fourth aim will investigate if augmentation of NLRP10 signaling can enhance host defense against K. pneumoniae. We anticipate this proposal using a unique combination of in vivo and in vitro systems, including KO mice, overexpression, and adoptive transfer strategies will enhance our understanding of the mechanisms by which NLRP10 modulates pulmonary host defense in both physiologic and pathologic conditions.

总结 肺部感染是脓毒症/败血症的主要原因，脓毒症/败血症造成相当大的死亡率和长期的死亡率。 长期发病率和卫生保健费用。成功清除呼吸道中的病原体是 依赖于有效的先天免疫反应。了解先天性免疫机制， 肺系统对于更好的免疫疗法或疫苗至关重要。信号级联触发了 先天免疫应答由促炎信号级联之间的微妙平衡组成， 并抵消抗炎信号。然而，目前还不清楚这些先天免疫是如何产生的。 级联汇聚以增加清除病原体，同时减少组织损伤。探索宿主 防御级联，我们已经集中在一个主要的革兰氏阴性细胞外病原体，克雷伯氏菌 肺炎，因为这种细菌诱导严重的肺部感染，随后是脓毒症;多重耐药 最近出现了新的病毒株，而且没有有效的疫苗。该提案将使用4个具体目标 为了检验总体假设：NLRP 10是通过IL-17 A的宿主防御途径的关键调节因子 可以作为预防或治疗的目标。第一个目标是探索NLRP 10的激活是否 增强细菌清除和中性粒细胞募集和功能。第二个目标是研究 NLRP 10依赖性IL-17的产生增强宿主防御。第三个目标是研究NLRP 10是否 破坏导致肺泡巨噬细胞的功能改变。第四个目标将调查， NLRP 10信号的增强可以增强宿主对K.肺炎。我们预料到这一点 使用体内和体外系统的独特组合的建议，包括KO小鼠，过表达， 和过继转移策略将提高我们对NLRP 10 在生理和病理条件下调节肺宿主防御。