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

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

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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，也是主要的传染病。在美国死亡，耗资超过170亿美元。抗生素抗性（AR）越来越多使肺炎治疗复杂化，并带来全球和全球的公共卫生危机。肺炎肺炎是一种常见的肺炎AR病原体，是一种极好的工具肺免疫的临床前建模。免疫调节疗法具有改变了癌症和自身免疫性领域，免疫疗法并未开发治疗包括肺炎在内的细菌感染。我们确定了类似Follistatin的1（FSTL-1），这是一种新颖的宿主免疫基因至关重要肺部防御。 FSTL-1介导的作用需要表达核激素受体4A1（NR4A1），一种新认识的K.肺炎（KP）肺的决定因素免疫。但是，FSTL-1-和NR4A1介导的肺防御的基础机制是未知的。发表的文献和我们的初步数据导致了以下假设 1，通过CD14结合，促进针对肺炎的肺先天免疫 1）将嗜中性粒细胞募集引导到肺部，2）增强中性粒细胞intrinsic， NR4A1依赖性细菌杀伤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的成分使用KP肺炎模型在K.肺炎感染期间的肺部，将测试FSTL-是否是否 1-依赖性嗜中性粒细胞募集是免疫细胞中性的，是否是RFSTL-1驱动的中性粒细胞募集是由受体CD14及其细胞需求介导的，以及 NR4A1在FSTL-1介导的肺免疫中的细胞特异性贡献。目标2）会确定FSTL-1如何通过测试增强中性粒细胞杀菌功能中性粒细胞 - 内膜FSTL-1表达是否需要抗菌效应子功能，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CD14对中性粒细胞的需求对此作用。目标3）将定义靶向NR4A1的治疗潜力。这将检查如果NR4A1缺乏症会损害中性粒细胞效应子的功能以及NR4A1是否刺激治疗可用于改善细菌性肺炎。累积地，拟议的工作将着重于填补知识的现有空白： FSTL-1介导的肺部防御的细胞和分子成分。