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

基本信息

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
项目类别：
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

项目摘要

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、巨噬细胞和脓肿分枝杆菌肺部感染的易感性非结核分枝杆菌 (NTM) 不会导致健康个体患病；然而，患有慢性病的人气道疾病容易发生肺部 NTM 感染 (pNTM)，从而加重症状负担并加速肺功能衰退。健康的肺部如何清除吸入的 NTM 以及患有此病的患者的原因气道疾病发生 pNTM 的风险增加，但人们对此仍知之甚少。我们的长期目标是了解巨噬细胞异质性如何导致慢性肺部疾病。这笔赠款的目的是描述吸入 NTM 最初与呼吸道巨噬细胞相互作用时发生的事件，以及确定细胞因子粒细胞巨噬细胞集落刺激因子 (GM-CSF) 如何促进清除 NTM 的。来自人类病例报告和缺乏 GM-CSF 的小鼠（GM-CSFKO 小鼠）的数据表明 GM-CSF 对于 pNTM 的免疫控制至关重要。我们选择研究 GM-CSF 在易感性中的作用脓肿分枝杆菌 (MAbsc) 是 pNTM 的重要原因，其数量正在增加普遍存在，并且根除尤其具有挑战性。我们的数据表明 GM-CSF 可以激活巨噬细胞杀死 MAbsc。在肺腔中，巨噬细胞可分为两大类：驻留型肺泡巨噬细胞（AlvMs）和募集的单核细胞衍生巨噬细胞（MDMs）。 ALVM 是本构型的暴露于肺泡上皮细胞产生的 GM-CSF。相比之下，人呼吸道中的大多数巨噬细胞患有慢性气道疾病的 MDM 是从血液中招募的，血液中存在低水平的 GM- 脑脊液。我们的中心假设是巨噬细胞必须被 GM-CSF 激活才能消除 NTM，并且在慢性气道疾病患者的气道中招募的 MDM 在杀死 NTM 方面的效果不如由于 GM-CSF 暴露不足而导致的 AlvM。我们将从三个具体目标来研究这一假设。目标1 将确定 GM-CSF 增强 MAbsc 巨噬细胞杀伤的机制，检验假设 GM-CSF 促进吞噬体成熟和吞噬溶酶体酸化。使用条件淘汰赛不同巨噬细胞亚群上缺乏 GM-CSF 受体的小鼠，目标 2 将检验以下假设：由 GM-CSF 编程的 AlvM 是负责控制健康肺部 MAbsc 的重要细胞。目的 3 将采用使用 MAbsc 包埋琼脂珠的小鼠气道感染模型来检验以下假设：气道中没有足够的 GM-CSF 来激活招募的 MDM 来形成杀分枝杆菌表型。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，并揭示肺部的位置如何影响招募的 MDM 的表型。结果来自拟议的研究将具有重要意义，因为它们将为使用免疫疗法来治疗非解决性问题提供信息慢性肺部疾病的感染，它们可以帮助预测哪些患有慢性肺部疾病的人发生 pNTM 的风险最高。