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)各自对全球疾病负担产生了重大贡献,因为在世界许多地区,快速工业增长和交通高端的流行性结核病会导致空气质量恶化。尽管流行病学研究表明,结核病的发生率增加与吸烟,职业暴露于二氧化硅或室内空气污染的关联,但我们所知的尚无研究研究城市空气污染在结核病发展和病理生物学机制中的作用。肺是细胞颗粒物(PM2.5)和结核分枝杆菌(M.TB)的主要入口,导致结核病的细菌,以及85%的TB病理。评估PM2.5对病原体特异性先天和适应性免疫反应的影响,特别是在人类肺中。我们在原代人血细胞中的初步研究表明,柴油排气中的PM2.5改变了细胞因子的产生和类似Toll样受体(TLR)介导的M.TB特异性细胞活化途径,并抑制了几种NF-KB和IRF-1介导的靶基因所需的适当的抗体抗体型宿主免疫免疫反应所需的pM2.5。基于这些研究,我们假设暴露于PM2.5会损害原发性人支气管肺泡细胞(BAC)的先天和适应性抗菌免疫效应子功能。该建议的具体目的是检查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BAC的吞噬作用和M.TB的生长控制中的作用,以及III)个人在Vivo PM2.5暴露及其与免疫效应中的关系在BAC中的关系。这些目标将如下:PM2.5将被收集,并具有健康的M.TB暴露和未暴露的研究受试者,具有有或没有免疫诊断的证据,这些证据表明潜在的M.TB感染以其TB病例的高度普遍性和高空气污染水平而闻名。 PM2.5将研究对M.TB诱导的促炎和抗炎细胞因子的产生和基因表达以及BAC中M.TB吞噬作用和生长控制的影响。 (1)对氧化应激的主要城市燃烧污染物和生物标志物以及(2)肺泡巨噬细胞的颗粒物负荷以及(3)时间活动的评估和(4)地理指标的测量值和(2)氧化应激的生物标志物以及(2)颗粒物质负载来确定研究对象的体内暴露。这些暴露的参数将与使用生物统计学方法的抗菌细菌BAC效应函数相关。因此,该提案将解决有关空气污染暴露对人类抗菌肺免疫的影响的重要差距。 PM2.5诱导的先天和适应性抗菌免疫反应的改变可能会带来对M.TB感染失去免疫控制的主要风险。鉴于空气污染和M.TB感染的广泛地理量表,从这项研究中获得的新知识将具有重大的全球健康影响。

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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