Follistatin-like 1 Mediated Host Defense in Bacterial Pneumonia

类卵泡抑素 1 介导细菌性肺炎中的宿主防御

基本信息

批准号：
10636904
负责人：
BRIAN T CAMPFIELD
金额：
$ 57.93万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636904
关键词：
Adult Agonist Anti-Bacterial Agents Antibiotic Resistance Antibiotics Asthma Autoimmunity Bacterial Antibiotic Resistance Bacterial Infections Bacterial Pneumonia Binding Biology Bronchoalveolar Lavage Fluid CD14 Antigen CD14 gene Cause of Death Cells Cessation of life Child Clinical Complex Critical Pathways Data Development Disease Follistatin Follistatin-Related Protein 1 Genes Genetic Transcription Health Health Care Costs Homeostasis Hospitalization Host Defense Immune Immune Targeting Immunity Immunomodulators Immunotherapy Impairment In Vitro Infection Inflammatory Klebsiella pneumoniae Knockout Mice Knowledge Lead Literature Lung Lung infections Malignant Neoplasms Mediating Mediator Modeling Molecular Morbidity - disease rate Mus NF-kappa B Natural Immunity Neutrophil Infiltration Nosocomial pneumonia Nuclear Hormone Receptors Outcome Study Pathogenesis Pathway interactions Phagocytosis Pneumonia Population Pre-Clinical Model Predisposition Production Public Health Publications Publishing Pulmonary Emphysema Pulmonary Fibrosis Recombinants Resistance to infection Respiratory Burst Role Signal Transduction Surface System TLR4 gene Testing Therapeutic Wild Type Mouse Work bactericide conditional knockout cost extracellular immune function immunomodulatory therapies improved in vivo in vivo Model innovation lung development mortality mucoid neutrophil novel novel strategies novel therapeutic intervention pathogen pneumonia model pneumonia treatment receptor response targeted treatment therapeutic target tool

项目摘要

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.

肺炎是儿童死亡的主要原因，也是导致儿童死亡的主要原因美国的死亡损失超过 170 亿美元。抗生素耐药性（AR）日益严重使肺炎治疗复杂化，并造成全国和世界范围的公共卫生危机。肺炎克雷伯菌是一种常见的引起肺炎的 AR 病原体，是一种极好的工具。肺免疫的临床前模型。虽然免疫调节疗法已免疫疗法改变了癌症和自身免疫领域，但尚未开发出来治疗细菌感染，包括肺炎。我们发现卵泡抑素样 1 (FSTL-1) 是一种新型宿主免疫基因，对于肺宿主防御。 FSTL-1介导的作用需要核激素的表达受体 4A1 (Nr4a1)，新认识的肺炎克雷伯菌 (Kp) 肺部决定因素免疫。然而，FSTL-1 和 Nr4a1 介导的肺宿主防御机制未知。已发表的文献和我们的初步数据得出这样的假设：FSTL- 1、通过CD14结合，促进肺部针对肺炎克雷伯菌的先天免疫通过 1) 引导中性粒细胞募集到肺部，2) 增强中性粒细胞内在， Nr4a1 依赖性细菌杀灭，将通过三个目标进行测试。目标 1) 将阐明 FSTL-1 介导的中性粒细胞募集到肺炎克雷伯菌感染期间使用肺炎克雷伯氏菌模型的肺部，将测试FSTL- 1 依赖性中性粒细胞募集是免疫细胞固有的，无论 rFSTL-1 驱动的中性粒细胞是否募集是由受体 CD14 及其中的细胞需求介导的，以及 Nr4a1 在 FSTL-1 介导的肺免疫中的细胞特异性贡献。目标 2) 将通过测试确定 FSTL-1 如何增强中性粒细胞内在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 依赖性中性粒细胞效应功能（吞噬作用、氧化爆发/ROS 产生、 NETosis 以及中性粒细胞 CD14 的需要才能实现这种效果。目标 3) 将定义肺炎克雷伯菌感染期间靶向 Nr4a1 的治疗潜力。这将检查 Nr4a1 缺乏是否会损害中性粒细胞效应功能以及 Nr4a1 是否会刺激可用于改善细菌性肺炎的治疗。总的来说，拟议的工作将侧重于填补现有的知识空白： FSTL-1 介导的肺部宿主防御的细胞和分子成分。