Follistatin-like 1 Mediated Host Defense in Bacterial Pneumonia

肺炎是导致儿童死亡的主要原因，也是儿童感染的主要原因。 在美国死亡，损失超过170亿美元。抗生素耐药性(AR)日益增加 使肺炎治疗复杂化，并构成国家和世界公共卫生危机。 肺炎克雷伯氏菌是一种常见的肺炎AR病原体，是治疗肺炎的良好工具 肺免疫的临床前模型。虽然免疫调节疗法有 改变了癌症和自身免疫领域，免疫疗法对于 治疗包括肺炎在内的细菌感染。 我们鉴定了卵泡抑素样蛋白1(FSTL-1)是一种新的宿主免疫基因，对 肺部宿主防御。FSTL-1介导的效应需要核激素的表达 新近发现的肺炎克雷伯菌肺炎性决定子受体4a1(Nr4a1) 豁免权。然而，FSTL-1和Nr4a1介导的肺宿主防御的机制 都是未知的。已发表的文献和我们的初步数据导致了FSTL- 1，通过CD14结合，促进肺对肺炎克雷伯菌的天然免疫 通过1)引导中性粒细胞重新聚集到肺和2)增强中性粒细胞的内在性， 依赖于Nr4a1的细菌杀灭，这将通过三个目标进行测试。 目的1)阐明FSTL-1介导的中性粒细胞募集的成分 在肺炎克雷伯菌感染期间，使用肺炎克雷伯菌肺炎模型将测试FSTL- 1依赖的中性粒细胞募集是免疫细胞固有的，无论是rFSTL-1驱动的中性粒细胞 募集是由受体CD14和其中的细胞要求以及 Nr4a1在FSTL-1介导的肺免疫中的细胞特异性作用目标2)意志 通过检测确定FSTL-1如何增强中性粒细胞固有杀菌功能 中性粒细胞固有的FSTL-1表达是否需要抗菌效应功能，FSTL-1 1依赖的中性粒细胞效应功能(吞噬、氧化猝发/ROS产生、 中性粒细胞表面CD14分子的表达及这种作用。目标3)将定义 靶向Nr4a1在肺炎克雷伯菌感染中的治疗潜力。这将检验 Nr4a1缺乏是否损害中性粒细胞效应器功能以及Nr4a1是否刺激 治疗可以用来改善细菌性肺炎。 总体而言，拟议的工作将侧重于填补现有的知识空白： FSTL-1介导的肺宿主防御的细胞和分子组成。

Pneumonia is the leading cause of death in children and the leading infectious cause of death in the U.S, costing more than $17 billion. Antibiotic resistance (AR) increasingly complicates pneumonia treatment and poses a national and worldwide public health crisis. Klebsiella pneumoniae, a common pneumonia-causing AR pathogen, is an excellent tool for preclinical modeling of pulmonary immunity. While immune modulation therapies have transformed the fields of cancer and autoimmunity, immunotherapy is undeveloped for the treatment of bacterial infections including pneumonia. We identified that follistatin-like 1 (FSTL-1) as is a novel host-immune gene critical for pulmonary host defense. The FSTL-1 mediated effect required expression of nuclear hormone receptor 4A1 (Nr4a1), a newly recognized determinant of K. pneumoniae (Kp) pulmonary immunity. However, the mechanism underlying FSTL-1- and Nr4a1-mediated lung host defense are unknown. Published literature and our preliminary data lead to the hypothesis that FSTL- 1, through CD14-binding, promotes pulmonary innate immunity against K. pneumoniae by 1) directing neutrophil recruitment to the lung and 2) enhancing neutrophil-intrinsic, Nr4a1-dependent bacterial killing, which will be tested via three Aims. Aim 1) will elucidate the constituents of FSTL-1 mediated neutrophil recruitment to the lung during K. pneumoniae infection using the Kp pneumonia model, will test whether FSTL- 1 -dependent neutrophil recruitment is immune cell-intrinsic, whether rFSTL-1-driven neutrophil recruitment is mediated by the receptor CD14 and the cellular requirements therein, as well as the cell-specific contribution of Nr4a1 in FSTL-1-mediated pulmonary immunity. Aim 2) will determine how FSTL-1 enhances neutrophil-intrinsic bactericidal function by testing whether neutrophil-intrinsic FSTL-1 expression is required antibacterial effector function, FSTL- 1-dependent neutrophil effector function (phagocytosis, oxidative burst/ROS production, NETosis and the requirement of CD14 on neutrophils for this effect. Aim 3) will define the therapeutic potential of targeting Nr4a1 during K. pneumoniae infection. This will examine if Nr4a1-deficiency impairs neutrophil effector functions and whether Nr4a1 stimulating treatment can be used to improve bacterial pneumonia. Cumulatively, the proposed work will focus on filling an existing gap in knowledge: the cellular and molecular constituents of FSTL-1-mediated pulmonary host-defense.