Air Pollution Particle Effects on Human Antimycobacterial Immunity

空气污染颗粒物对人体抗分枝杆菌免疫的影响

基本信息

  • 批准号:
    8686842
  • 负责人:
  • 金额:
    $ 60.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Air pollution and tuberculosis (TB) each contribute significantly to global disease burden as deteriorating air quality from rapid industrial growth and traffic collide with high levels of endemic TB in many parts of the world. Although epidemiological studies have shown associations of increased incidence of TB with cigarette smoking, occupational exposure to silica, or indoor air pollution, no studies to our knowledge have examined the role of urban air pollution exposure in the development of TB and underlying pathobiological mechanisms. The lungs are the primary portal of entry for fine urban particulate matter (PM2.5) and Mycobacterium tuberculosis (M.tb), the bacterium that causes TB, and the site of 85% of TB pathology. Studies evaluating PM2.5 effects on pathogen-specific innate and adaptive immune responses, particularly in the human lungs, are lacking. Our preliminary studies in primary human blood cells have shown that PM2.5 from diesel exhaust alters cytokine production and toll-like receptor (TLR)-mediated M.tb-specific cell activation pathways with suppression of several NF-kB and IRF-1-mediated target genes required for appropriate antimycobacterial host immune responses. Based on these studies, we hypothesize that exposure to PM2.5 impairs innate and adaptive antimycobacterial immune effector functions of primary human bronchoalveolar cells (BACs). Specific aims of this proposal are to examine i) PM2.5-induced cellular toxicity and PM2.5 effects on M.tb-specific immunity, ii) the role of PM2.5 in altering phagocytosis and growth control of M.tb by human BACs, and iii) personal in vivo PM2.5 exposure and its relationship to immune effector functions in BAC. These aims will be addressed as follows: PM2.5 will be collected and healthy M.tb-exposed and unexposed study subjects with and without immunodiagnostic evidence of latent M.tb infection recruited in a megacity known for its high prevalence of TB cases and high air pollution levels. PM2.5 effects will be studied on M.tb-induced pro- and anti-inflammatory cytokine production and gene expression, and on M.tb phagocytosis and growth control in BACs. Measurements of (1) urinary metabolites for major urban combustion pollutants and biomarkers of oxidative stress and (2) particulate matter load of alveolar macrophages and assessments of (3) time activity and (4) geographical indicators will be used to determine in vivo exposure of the study subjects. These parameters of exposure will be correlated with the antimycobacterial BAC effector functions using biostatistical methods. Thus, this proposal will address a crucial gap in knowledge about the effects of air pollution exposure on human antimicrobial lung immunity. PM2.5-induced alterations of innate and adaptive antimycobacterial immune responses may confer a major risk of loss of immunological control over M.tb infection. Given the wide geographical scales for both air pollution and M.tb infections, new knowledge to be gained from this study will have significant global health implications.
描述(由申请人提供):空气污染和结核病 (TB) 均对全球疾病负担造成重大影响,因为快速工业增长和交通造成的空气质量恶化与世界许多地区高水平的地方性结核病相冲突。尽管流行病学研究表明结核病发病率增加与吸烟、职业接触二氧化硅或室内空气污染有关,但据我们所知,尚无研究探讨城市空气污染暴露在结核病发展中的作用以及潜在的病理生物学机制。肺部是城市细颗粒物 (PM2.5) 和结核分枝杆菌 (M.tb) 的主要入口,结核分枝杆菌是引起结核病的细菌,也是 85% 结核病病理发生的部位。目前还缺乏评估 PM2.5 对病原体特异性先天和适应性免疫反应(尤其是人类肺部)影响的研究。我们对原代人类血细胞的初步研究表明,柴油机尾气中的 PM2.5 会改变细胞因子的产生和 Toll 样受体 (TLR) 介导的 M.tb 特异性细胞激活途径,并抑制多种 NF-kB 和 IRF-1-介导适当的抗分枝杆菌宿主免疫反应所需的靶基因。基于这些研究,我们假设暴露于 PM2.5 会损害原代人支气管肺泡细胞 (BAC) 的先天性和适应性抗分枝杆菌免疫效应功能。该提案的具体目的是检查 i) PM2.5 诱导的细胞毒性和 PM2.5 对 M.tb 特异性免疫的影响,ii) PM2.5 在改变人类对 M.tb 的吞噬作用和生长控制中的作用BAC,以及 iii) 个人体内 PM2.5 暴露及其与 BAC 中免疫效应器功能的关系。这些目空气污染程度。将研究 PM2.5 对 M.tb 诱导的促炎和抗炎细胞因子产生和基因表达的影响,以及对 BAC 中 M.tb 吞噬作用和生长控制的影响。将使用 (1) 主要城市燃烧污染物的尿代谢物和氧化应激生物标志物的测量和 (2) 肺泡巨噬细胞的颗粒物负荷以及 (3) 时间活动和 (4) 地理指标的评估来确定体内暴露研究对象。使用生物统计学方法将这些暴露参数与抗分枝杆菌 BAC 效应子功能相关联。因此,该提案将解决关于空气污染暴露对人类抗菌肺免疫力影响的知识空白。 PM2.5 引起的先天性和适应性抗分枝杆菌免疫反应的改变可能会带来失去对结核分枝杆菌感染的免疫控制的重大风险。鉴于空气污染和结核分枝杆菌感染的地理范围广泛,从这项研究中获得的新知识将对全球健康产生重大影响。

项目成果

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STEPHAN K SCHWANDER其他文献

STEPHAN K SCHWANDER的其他文献

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{{ truncateString('STEPHAN K SCHWANDER', 18)}}的其他基金

Air Pollution Particle Effects on Human Antimycobacterial Immunity
空气污染颗粒物对人体抗分枝杆菌免疫的影响
  • 批准号:
    9121809
  • 财政年份:
    2015
  • 资助金额:
    $ 60.22万
  • 项目类别:
Air Pollution Particle Effects on Human Antimycobacterial Immunity
空气污染颗粒物对人体抗分枝杆菌免疫的影响
  • 批准号:
    8736356
  • 财政年份:
    2012
  • 资助金额:
    $ 60.22万
  • 项目类别:
Air Pollution Particle Effects on Human Antimycobacterial Immunity
空气污染颗粒物对人体抗分枝杆菌免疫的影响
  • 批准号:
    8926494
  • 财政年份:
    2012
  • 资助金额:
    $ 60.22万
  • 项目类别:
Air Pollution Effects on Transmission of Mycobacterium tuberculosis in Urban Slum Community in Uganda
乌干达城市贫民窟社区空气污染对结核分枝杆菌传播的影响
  • 批准号:
    10367013
  • 财政年份:
    2012
  • 资助金额:
    $ 60.22万
  • 项目类别:
Air Pollution Particle Effects on Human Antimycobacterial Immunity
空气污染颗粒物对人体抗分枝杆菌免疫的影响
  • 批准号:
    8239250
  • 财政年份:
    2012
  • 资助金额:
    $ 60.22万
  • 项目类别:
Air Pollution Particle Effects on Human Antimycobacterial Immunity
空气污染颗粒物对人体抗分枝杆菌免疫的影响
  • 批准号:
    8538384
  • 财政年份:
    2012
  • 资助金额:
    $ 60.22万
  • 项目类别:
Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis
柴油机尾气颗粒对人体结核分枝杆菌免疫的影响
  • 批准号:
    7512585
  • 财政年份:
    2008
  • 资助金额:
    $ 60.22万
  • 项目类别:
Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis
柴油机尾气颗粒对人体结核分枝杆菌免疫的影响
  • 批准号:
    8075141
  • 财政年份:
    2008
  • 资助金额:
    $ 60.22万
  • 项目类别:
Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis
柴油机尾气颗粒对人体结核分枝杆菌免疫的影响
  • 批准号:
    7679001
  • 财政年份:
    2008
  • 资助金额:
    $ 60.22万
  • 项目类别:
Pathogen Specific Immunity in Sarcoidosis
结节病的病原体特异性免疫
  • 批准号:
    6815578
  • 财政年份:
    2004
  • 资助金额:
    $ 60.22万
  • 项目类别:

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