GM-CSF, macrophages, and susceptibility to Mycobacterium abscessus pulmonary infection

GM-CSF、巨噬细胞和脓肿分枝杆菌肺部感染的易感性

• 批准号: 10637279
• 负责人: Katherine B Hisert
• 金额: $ 61.57万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637279
• 关键词: Acceleration; Address; Agar; Airway Disease; Alveolar Macrophages; Alveolus; Animal Model; Bathing; Blood; Blood Circulation; Bronchiectasis; Case Study; Categories; Cells; Chronic lung disease; Clinical; Colony Stimulating Factor Activation; Data; Development; Disease; Disease susceptibility; Distal; Environment; Epithelial Cells; Event; Exposure to; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Growth; Heterogeneity; Human; Immune; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Inhalation; Knockout Mice; Knowledge; Legal patent; Location; Lung; Lung infections; Macrophage; Macrophage Colony-Stimulating Factor; Macrophage-Activating Factors; Measures; Mediating; Methods; Modeling; Molecular; Mucociliary Clearance; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Patients; Persons; Phagolysosome; Phagosomes; Phenotype; Predisposition; Prevalence; Production; Reporter; Research; Respiratory System; Respiratory Tract Infections; Risk; Role; Stains; Symptoms; Testing; airway obstruction; alveolar epithelium; antimicrobial; chronic respiratory disease; conditional knockout; cytokine; enhancing factor; high risk; human data; improved; innovation; monocyte; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel; novel therapeutics; opportunistic pathogen; pathogen; pulmonary function decline; recruit; Acceleration; Address; Agar; Airway Disease; Alveolar Macrophages; Alveolus; Animal Model; Bathing; Blood; Blood Circulation; Bronchiectasis; Case Study; Categories; Cells; Chronic lung disease; Clinical; Colony Stimulating Factor Activation; Data; Development; Disease; Disease susceptibility; Distal; Environment; Epithelial Cells; Event; Exposure to; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Growth; Heterogeneity; Human; Immune; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Inhalation; Knockout Mice; Knowledge; Legal patent; Location; Lung; Lung infections; Macrophage; Macrophage Colony-Stimulating Factor; Macrophage-Activating Factors; Measures; Mediating; Methods; Modeling; Molecular; Mucociliary Clearance; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Patients; Persons; Phagolysosome; Phagosomes; Phenotype; Predisposition; Prevalence; Production; Reporter; Research; Respiratory System; Respiratory Tract Infections; Risk; Role; Stains; Symptoms; Testing; airway obstruction; alveolar epithelium; antimicrobial; chronic respiratory disease; conditional knockout; cytokine; enhancing factor; high risk; human data; improved; innovation; monocyte; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel; novel therapeutics; opportunistic pathogen; pathogen; pulmonary function decline; recruit

GM-CSF, macrophages, and susceptibility to Mycobacterium abscessus pulmonary infection Nontuberculous mycobacteria (NTM) do not cause disease in healthy individuals; however, people with chronic airways diseases are susceptible to developing pulmonary NTM infections (pNTM), which increase symptom burden and accelerate lung function decline. How the healthy lung clears inhaled NTM and why individuals with airways disease are at increased risk of developing pNTM remain poorly understood. Our long term goal is to understand how macrophage heterogeneity contributes to chronic lung diseases. The objective of this grant is to characterize events that occur when inhaled NTM initially interact with respiratory tract macrophages, and determine how the cytokine granulocyte macrophage colony stimulating factor (GM-CSF) promotes clearance of NTM. Data from human case reports and mice lacking GM-CSF (GM-CSFKO mice) indicate that GM-CSF is essential for immune control of pNTM. We have chosen to study the role of GM-CSF in susceptibility to Mycobacterium abscessus (MAbsc) as this species causes a significant portion of pNTM, is increasing in prevalence, and is especially challenging to eradicate. Our data demonstrate that GM-CSF can activate macrophages to kill MAbsc. In lung airspaces, macrophages can be grouped into two main categories: resident alveolar macrophages (AlvMs) and recruited monocyte-derived macrophages (MDMs). AlvMs are constitutively exposed to GM-CSF produced by alveolar epithelial cells. In contrast, most macrophages in airways of people with chronic airways disease are MDMs recruited from the bloodstream, a compartment with low levels of GM- CSF. Our central hypothesis is that macrophages must be activated by GM-CSF to eliminate NTM, and that MDMs recruited to the airways in people with chronic airways disease are less effective at killing NTM than AlvMs due to insufficient exposure to GM-CSF. We will investigate this hypothesis in three specific aims. Aim 1 will determine the mechanism by which GM-CSF enhances macrophage killing of MAbsc, testing the hypothesis that GM-CSF promotes phagosomal maturation and phagolysosomal acidification. Using conditional knockout mice that lack the GM-CSF receptor on different macrophage subsets, Aim 2 will test the hypothesis that resident AlvMs programmed by GM-CSF are the essential cells responsible for control of MAbsc in the healthy lung. Aim 3 will employ a mouse model of airway infection using MAbsc-embedded agar beads to test the hypothesis that there is insufficient GM-CSF in the airways to activate recruited MDMs to develop mycobacteriocidal phenotypes. These studies are innovative, as they will determine the mechanisms by which GM-CSF enhances macrophage killing of MAbsc, and reveal how location in the lung influences phenotypes of recruited MDMs. The results from the proposed research will be significant, as they will inform use of immune therapies to treat non-resolving infection in chronic lung diseases, and they could help predict which individuals with chronic lung diseases are at highest risk for developing pNTM.

GM-CSF，巨噬细胞和对脓肿肺部感染分枝杆菌的敏感性 非结核分枝杆菌（NTM）不会引起健康个体的疾病；但是，患有慢性的人 气道疾病容易患肺NTM感染（PNTM），这会增加症状 负担和加速肺功能下降。健康的肺如何清除吸入的NTM以及为什么患有 气道疾病的发展风险增加，人们的了解程度较低。我们的长期目标是 了解巨噬细胞异质性如何有助于慢性肺部疾病。这笔赠款的目的是 表征当吸入NTM最初与呼吸道巨噬细胞相互作用时发生的事件，并且 确定细胞因子粒细胞巨噬细胞刺激因子（GM-CSF）如何促进清除 NTM。来自人类病例报告的数据和缺乏GM-CSF（GM-CSFKO小鼠）的小鼠表明GM-CSF是 对PNTM的免疫控制至关重要。我们选择研究GM-CSF在易感性中的作用 腹肌分枝杆菌（MABSC）由于该物种引起了很大的PNTM，因此正在增加 流行率，尤其是根除的挑战。我们的数据表明GM-CSF可以激活 巨噬细胞杀死MABSC。在肺空间中，巨噬细胞可以分为两个主要类别：居民 肺泡巨噬细胞（ALVM）和募集的单核细胞衍生的巨噬细胞（MDMS）。 ALVM是组成性的 暴露于肺泡上皮细胞产生的GM-CSF。相比之下，大多数巨噬细胞在人的气道中 慢性气道疾病是从血液中招募的MDM，这是GM水平较低的隔室 CSF。我们的中心假设是，GM-CSF必须激活巨噬细胞以消除NTM，并且 在患有慢性气道疾病患者的航空公司招募到航空公司的MDMS杀死NTM的效果不如 由于对GM-CSF的暴露不足而导致的ALVM。我们将以三个具体目标研究这一假设。目标1 将确定GM-CSF增强MABSC巨噬细胞杀死的机制，检验假设 GM-CSF促进了吞噬体成熟和吞噬酸性酸化。使用有条件的淘汰赛 AIM 2在不同巨噬细胞子集上缺乏GM-CSF受体的小鼠将检验居民的假设 由GM-CSF编程的ALVM是负责控制健康肺中MABSC的必需细胞。目的 3将使用MABSC填充的琼脂珠采用气道感染的小鼠模型来检验以下假设。 气道中的GM-CSF不足以激活招募的MDMs开发分枝杆菌表型。 这些研究具有创新性，因为它们将确定GM-CSF增强巨噬细胞的机制 杀死MABSC，并揭示肺中的位置如何影响招募MDM的表型。结果 拟议的研究将是重要的，因为他们将告知使用免疫疗法来治疗非分辨率 慢性肺部疾病的感染，它们可以帮助预测哪些慢性肺部疾病的人是 开发PNTM的风险最高。