Project 1

项目摘要 脓毒症是世界范围内发病率和死亡率的主要原因， 负担肺炎经常与脓毒症相关，脓毒症的特征是非消退性肺炎。 过度炎症然而，调节复杂的肺环境的特定宿主成分 在本研究中观察到的病原体清除和炎症持续存在以及组织破坏之间的平衡， 免疫紊乱还不清楚。这种知识对于制定有效的预防措施至关重要 和/或治疗策略。拟议研究的长期目标是 表征调节病原体清除的肺先天免疫组分的功能， 克雷伯氏肺炎菌引起的肺炎脓毒症小鼠模型中初始炎症的消退 （KPn）。吞噬细胞在脓毒症的病理生理学中起重要作用，它通过调节初始吞噬细胞的诱导， 对感染的保护性炎症反应以及这种炎症的消退以恢复体内平衡。 通过吞噬作用摄取和清除病原体以及通过吞噬作用摄取和清除死细胞是两个重要的 吞噬细胞功能;这些中的任一个的失调可导致持续性炎症，如在脓毒症中所见。 由吞噬细胞表达的先天性免疫C型凝集素受体正在成为免疫系统中的主要参与者。 免疫调节虽然脓毒症起源于先天性免疫紊乱，但CLRs作为先天性免疫紊乱的作用可能与其自身免疫紊乱有关。 受体在调节脓毒症中的作用在很大程度上尚未探索。在这方面，我们已经表明：1）动力学上调 两种CLRs Clec 4d和Clec 4 e在经历肺炎脓毒症的KPn感染小鼠的肺中; 2）增加 Clec 4d-/-和Clec 4 e-/-小鼠对KPn感染的易感性; 3）炎症反应过度和增加 感染的Clec 4d-/-和Clec 4 e-/-小鼠中的局部和全身器官负荷;以及4）中性粒细胞 在不存在Clec 4 e的情况下介导的细菌吞噬作用，而在Clec 4d中， 缺陷为了阐明Clec 4d和Clec 4 e在抗肿瘤中发挥保护作用的机制， 目的：1）鉴定Clec 4 e介导的KPn吞噬作用， 下游事件。目的2）阐明Clec 4d介导的细胞增殖调节机制， 肺炎克雷伯氏菌感染时的炎症。目的3）研究早期事件的机制 Clec 4 e和Clec 4d介导的感染控制的晚期事件（吞噬作用）和晚期事件（吞噬作用）， 炎症是协调的。这些研究的成功完成不仅将填补我们 了解肺炎脓毒症的先天性免疫反应，但将有意义，在寻找成功的 治疗其他免疫疾病，其中肆无忌惮的炎症是疾病的根本原因。

Project Summary Pneumonic sepsis is a leading cause of morbidity and mortality worldwide and poses a major healthcare burden. Pneumonia is frequently associated with sepsis which is characterized by a non-resolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the intricate balance between pathogen clearance and perpetuation of inflammation and tissue destruction observed in this immune disorder are not clearly understood. This knowledge is critical for developing effective prevention and/or treatment strategies for this deadly immune disorder. The long term goal of the proposed research is to characterize the functioning of pulmonary innate immune components regulating the pathogen clearance and resolution of initial inflammation in a mouse model of pneumonic sepsis caused by Klebsiella pneumonia (KPn). Phagocytic cells play an important role in pathophysiology of sepsis by regulating the induction of initial protective inflammatory response to infection as well as resolution of this inflammation to restore homeostasis. Uptake and clearance of pathogen by phagocytosis and dead cells by efferocytosis are two important phagocytic cell functions; deregulation of either of these can lead to persistent inflammation as seen in sepsis. Innate immune C-type lectin receptors expressed by phagocytic cells are emerging as major players in immune regulation. Although sepsis has its origin in innate immune derangements, the role of CLRs as innate receptors in modulation of sepsis is largely unexplored. In this regard we have shown: 1) kinetic upregulation of two CLRs Clec4d and Clec4e in the lungs of KPn infected mice undergoing pneumonic sepsis; 2) increased susceptibility of Clec4d-/- and Clec4e-/- mice to KPn infection; 3) hyperinflammatory response and increased local and systemic organs burden in infected Clec4d-/- and Clec4e-/- mice; and 4) a defect in neutrophil mediated bacterial phagocytosis in the absence of Clec4e while an impairment of dead cell uptake in Clec4d deficiency. To elucidate the mechanism by which Clec4d and Clec4e play a protective role in defense against pneumonic sepsis, we are proposing to: Aim 1) Characterize Clec4e-mediated phagocytosis of KPn and the downstream events.; Aim 2) Elucidate the mechanisms of Clec4d-mediated regulation of efferocytosis and inflammation during KPn infection.; and Aim 3) Investigate the mechanism by which the early event (phagocytosis) and the late event (efferocytosis) of Clec4e- and Clec4d-mediated control of infection and inflammation are coordinated. The successful completion of these studies will not only fill a gap in our understanding of innate immune responses in pneumonic sepsis but will have implications in finding successful therapies for other immune disorders as well, where unbridled inflammation is the root cause of disease.