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:
  • 金额:
    $ 61.57万
  • 依托单位:
  • 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

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、巨噬细胞与结核分枝杆菌肺部感染易感性 非结核分枝杆菌(NTM)在健康个体中不会引起疾病;然而, 呼吸道疾病易发生肺部NTM感染(pNTM), 加重负担,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NTM的人 气道疾病发展为pNTM的风险增加仍然知之甚少。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。该补助金的目的是 表征吸入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 的NTM。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是 对pNTM的免疫控制至关重要。我们选择了研究GM-CSF在易感性中的作用, 结核分枝杆菌(MAbsc)作为该物种引起pNTM的显著部分,在 这是一个普遍存在的问题,尤其难以根除。我们的数据表明GM-CSF可以激活 巨噬细胞杀死MAbsc。在肺的空气空间中,巨噬细胞可以分为两大类: 肺泡巨噬细胞(AlvM)和募集的单核细胞衍生的巨噬细胞(MDM)。AlvM在结构上是 暴露于肺泡上皮细胞产生的GM-CSF。相比之下,大多数人气道中的巨噬细胞 患有慢性气道疾病的人是从血液中招募的MDM,血液中含有低水平的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, 在慢性气道疾病患者的气道中招募的MDM在杀死NTM方面不如 由于GM-CSF暴露不足导致的AlvM。我们将在三个具体目标中研究这一假设。要求1 将确定GM-CSF增强MAbsc的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。使用条件敲除 在不同的巨噬细胞亚群上缺乏GM-CSF受体的小鼠中,Aim 2将检验以下假设: 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包埋的琼脂珠粒使用气道感染的小鼠模型来测试以下假设: 气道中没有足够的GM-CSF来激活募集的MDM以产生杀分枝杆菌表型。 这些研究是创新的,因为它们将确定GM-CSF增强巨噬细胞增殖的机制。 杀死MAbsc,并揭示肺中的位置如何影响招募的MDM的表型。的结果 拟议的研究将具有重要意义,因为它们将为使用免疫疗法治疗非消退性 他们可以帮助预测哪些患有慢性肺部疾病的人 pNTM的风险最高

项目成果

期刊论文数量(1)
专著数量(0)
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Katherine B Hisert其他文献

Katherine B Hisert的其他文献

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{{ truncateString('Katherine B Hisert', 18)}}的其他基金

Modulating macrophage-mediated Inflammation in cystic fibrosis
调节囊性纤维化中巨噬细胞介导的炎症
  • 批准号:
    9893893
  • 财政年份:
    2018
  • 资助金额:
    $ 61.57万
  • 项目类别:
Modulating macrophage-mediated Inflammation in cystic fibrosis
调节囊性纤维化中巨噬细胞介导的炎症
  • 批准号:
    10371188
  • 财政年份:
    2018
  • 资助金额:
    $ 61.57万
  • 项目类别:

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