Innate Immunity in Lung Infection-induced Sepsis

摘要 肺部感染是败血症/败血症的主要原因，可造成大量死亡和长期- 足月发病率和医疗保健费用。从呼吸道成功清除病原体是 依赖有效的先天免疫反应。了解人的先天免疫机制 肺部系统对于更好的免疫疗法或疫苗至关重要。信令级联触发 先天免疫反应由促炎信号级联、 并对抗抗炎信号。然而，目前还不太清楚这些先天免疫是如何 级联聚合以增加明确的病原体，同时减少组织损害。要探索主机 防御级联，我们关注的是一种主要的革兰氏阴性胞外病原体，克雷伯氏菌 肺炎，因为这种细菌会导致严重的肺部感染和败血症；多重耐药 最近出现了新的毒株；目前还没有有效的疫苗。该提案将使用4个具体目标 检验整体假设：NLRP10是通过IL-17A的宿主防御途径的关键调节因子 可以作为预防或治疗的靶点。第一个目标将探索NLRP10的激活 增强细菌清除和中性粒细胞募集和功能。第二个目标将研究是否 依赖于NLRP10的IL-17的产生增强了宿主的防御。第三个目标将检查NLRP10是否 破坏会导致肺泡巨噬细胞的功能改变。第四个目标将调查是否 NLRP10信号的增强可以增强宿主对肺炎克雷伯菌的抵抗力。我们预料到了这一点 建议使用体内和体外系统的独特组合，包括KO小鼠，过度表达， 而采用的迁移策略将增强我们对NLRP10机制的理解 在生理和病理条件下调节肺宿主防御。

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.