Project 1

项目摘要 肺炎败血症是全世界发病率和死亡率的主要原因，并构成主要的医疗保健。 负担。肺炎经常与败血症有关，败血症的特征是 过度炎症。然而，调节复杂的肺环境的特定宿主成分 在此观察到病原体清除与炎症和组织破坏之间的平衡 免疫性疾病目前还不清楚。这一知识对于制定有效的预防措施至关重要。 和/或治疗这种致命免疫疾病的策略。拟议研究的长期目标是 描述调节病原体清除和肺固有免疫成分的功能 克雷伯氏菌肺炎所致肺炎脓毒症小鼠模型的初始炎症消退 (KPN)。吞噬细胞在脓毒症的病理生理机制中起重要作用 对感染的保护性炎症反应以及对这种炎症的消解以恢复体内平衡。 通过吞噬作用摄取和清除病原体和通过胞吐作用清除死亡细胞是两个重要的过程。 吞噬细胞的功能；放松这两种功能中的任何一种都会导致持续的炎症，就像脓毒症一样。 吞噬细胞表达的天然免疫C型凝集素受体正在成为 免疫调节。尽管脓毒症起源于先天免疫紊乱，但作为先天免疫紊乱的CLR的作用 受体在脓毒症中的调节作用在很大程度上还没有被探索。在这方面，我们已经表明：1)动力学上调 KPN感染肺炎脓毒症小鼠肺组织中Clec4d和Clec4e的两个CLR；2)增加 Clec4d-/-和Clec4e-/-小鼠对KPN感染的易感性；3)高炎症反应和增加 感染Clec4d-/-和Clec4e-/-小鼠的局部和全身器官负担；4)中性粒细胞缺陷 在没有Clec4e的情况下介导的细菌吞噬作用，而对Clec4d中的死亡细胞摄取的损害 缺乏症。阐明Clec4d和Clec4e在机体防御中起保护作用的机制 肺炎败血症，我们建议：目的1)表征Clec4e介导的KPN吞噬作用和 下游事件。目的2)阐明Clec4d介导的泡泡吞噬调节机制和 KPN感染过程中的炎症；以及目的3)研究早期事件发生的机制 (吞噬作用)和Clec4e和Clec4d介导的感染和感染控制的晚期事件(泡沫化) 炎症是相互协调的。这些研究的成功完成不仅将填补我们在 了解肺炎脓毒症的先天免疫反应，但将对成功发现有意义 其他免疫疾病的治疗也是如此，在这些疾病中，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.