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。 死亡在美国，成本超过170亿美元。抗生素耐药性（AR）日益严重 使肺炎治疗复杂化，并造成国家和世界范围的公共卫生危机。 肺炎克雷伯氏菌是一种常见的肺炎致AR病原体， 肺免疫的临床前建模。虽然免疫调节疗法具有 虽然免疫疗法改变了癌症和自身免疫领域，但免疫疗法尚未开发， 治疗细菌感染，包括肺炎。 我们发现卵泡抑素样1（FSTL-1）是一个新的宿主免疫基因， 肺宿主防御FSTL-1介导的作用需要核激素的表达 受体4A 1（Nr 4a 1）是新近发现的K.肺炎（Kp）肺 免疫力然而，FSTL-1和Nr 4a 1介导的肺宿主防御的潜在机制， 是未知的。已发表的文献和我们的初步数据导致的假设，FSTL- 1通过与CD 14结合，促进肺天然免疫。肺炎 通过1）引导中性粒细胞募集到肺和2）增强中性粒细胞-内源性， Nr 4a 1依赖性细菌杀伤，将通过三个目标进行测试。 目的1）将阐明FSTL-1介导的中性粒细胞募集到细胞的组成部分， K.使用Kp肺炎模型的肺炎感染，将测试FSTL- 1依赖的中性粒细胞募集是免疫细胞内在的，无论是rFSTL-1驱动的中性粒细胞 募集由受体CD 14和其中的细胞需求介导，以及 Nr 4a 1在FSTL-1介导的肺免疫中的细胞特异性贡献。（2）将 通过测试确定FSTL-1如何增强嗜中性粒细胞固有的杀菌功能， 是否需要抗菌素-内在FSTL-1表达的抗菌效应功能，FSTL- 1-依赖性中性粒细胞效应子功能（吞噬作用，氧化爆发/ROS产生， NETosis和中性粒细胞上的CD 14对于这种作用的需求。目标3）将定义 在K.肺炎感染。这将检查 如果Nr 4a 1缺乏损害中性粒细胞效应子功能， 治疗可用于改善细菌性肺炎。 拟议的工作将逐步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成分。

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.