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

基本信息

批准号：
7512585
负责人：
STEPHAN K SCHWANDER
金额：
$ 23.4万
依托单位：
UNIV OF MED/DENT NJ-SCH OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7512585
关键词：
6-carboxyfluorescein diacetate Acute Address Affect Air Pollutants Air Pollution Antigens Antimycobacterial Agents Bacteria Biological Biological Models Blood Blood Cells Blood specimen Breathing Cell Proliferation Cell model Cells Cities Clinical Colony-Forming Units Assay Condition Data Diesel Exhaust Disease Dose Effector Cell Endotoxins Epithelial Cells Esters Exposure to Gene Expression Grant Growth Health Hour Human Human body Immune Immune response Immunity In Vitro Industry Infection Inhalation Exposure Interferon Type II Interleukin-10 Interleukin-6 Interleukins Kinetics Lipopolysaccharides Listeria monocytogenes Lung Mediating Memory Mining Modeling Molecular Monokines Morbidity - disease rate Mycobacterium tuberculosis Occupational Exposure Particulate Particulate Matter Peripheral Blood Mononuclear Cell Personal Satisfaction Persons Phagocytes Population Predisposition Production Public Health Receptor Gene Receptor Signaling Regulation Respiration Respiratory Tract Infections Respiratory physiology Rodent Signal Pathway Signaling Pathway Gene Stimulus Study Subject System T-Lymphocyte Time Toll-Like Receptor Pathway Toll-like receptors Translating Tuberculosis Tumor Necrosis Factor-alpha Virus Vulnerable Populations Whole Blood cytokine dosage enzyme linked immunospot assay healthy volunteer human TNF protein in vivo killings macrophage monocyte mortality mycobacterial novel particle particle exposure pathogen peripheral blood pollutant receptor expression research study response size transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Air pollution and tuberculosis (TB) each present major challenges to public health and specifically to lung health globally. This grant will address the pressing question of whether air pollutants can acutely alter human antimycobacterial immunity. [PARAGRAPH] Urban air pollution, contributes substantially to morbidity and mortality worldwide. Diesel Exhaust Particles (DEP) from diesel engines are generated by various industries, contribute to 40% of particulate respirable matter in big cities and accumulate in underground mines. DEP represent an important model pollutant for the study of biological and health effects of respirable particulate matter (PM). [PARAGRAPH] There is mounting evidence that DEP (PM) alters the function of respiratory immune cells and increases susceptibility to infectious pathogens such as viruses and bacteria. Experimental aerogenic infections with intracellular bacteria such as Mycobacterium tuberculosis (M.tb), Bacille Calmette Guirin (BCG) or Listeria monocytogenes result in increased pulmonary bacterial burden in rodents exposed to DEP. [PARAGRAPH] We have novel preliminary data that indicate that human blood phagocytes take up both M.tb and DEP. During simultaneous addition of DEP and M.tb, M.tb-induced cytokine production from peripheral blood cells is altered (IFN-gamma, TNF-alpha, IL-6 decreased, IL-10 increased) in a DEP dose-dependent manner. Exposure to DEP 20 hours before M.tb infection abrogated M.tb induced IL-6 and IL-10 production, perhaps indicating a DEP-induced state of cellular unresponsiveness/tolerance to subsequent stimuli, similar to endotoxin tolerance. Our unique preliminary studies in healthy volunteers after DEP inhalation exposure show increased M.tb-induced IFN-gamma, and decreased M.tb-induced IL-6 and IL-10 release. Both DEP in vitro addition and in vivo exposure studies indicate that DEP decreases the capacity of blood cells to control M.tb growth in vitro. [PARAGRAPH] The proposed studies in this grant differ from previous DEP (PM) effect studies in several important ways. DEP effects will be studied (1) on immunity to a pathogen of overriding public health importance (M.tb), (2) in humans with and without pathogen (M.tb)-specific memory immunity, and (3) in in vitro and in vivo DEP-exposed primary human blood cells. We propose to expand our studies of dose and time kinetic effects of DEP exposure. Changes in antigen-specific cytokine production, M.tb-induced cell proliferation, growth control of M.tb and Th1 and Th2 as well as toll like receptor (TLR) gene expression and their signaling pathways will be assessed. [PARAGRAPH] We hypothesize that the combined effects of PM (DEP) and M.tb on the human host may alter antimycobacterial immune responses thus increasing susceptibility to M.tb infection and TB disease with potentially important public health effects on a population level. PUBLIC HEALTH RELEVANCE: Air pollution and tuberculosis (TB) present public health challenges to lung health on a global scale. This grant will address whether air pollutants can severely alter the human bodily defenses against tuberculosis. We will investigate how the combination of diesel exhaust particles and tuberculosis on the human body affect human immune response thus increasing vulnerability to tuberculosis infection and TB disease which may impact on the public health on a population level.

描述（由申请人提供）：空气污染和结核病 (TB) 都对全球公共卫生尤其是肺部健康构成重大挑战。这笔赠款将解决空气污染物是否会急剧改变人类抗分枝杆菌免疫力的紧迫问题。 [段落] 城市空气污染极大地导致了全世界的发病率和死亡率。柴油发动机产生的柴油机尾气颗粒 (DEP) 由各个行业产生，占大城市可吸入颗粒物的 40%，并在地下矿井中积累。 DEP 是研究可吸入颗粒物 (PM) 生物和健康影响的重要模型污染物。 [段落] 越来越多的证据表明 DEP (PM) 会改变呼吸道免疫细胞的功能并增加对病毒和细菌等传染性病原体的易感性。细胞内细菌（例如结核分枝杆菌 (M.tb)、卡介苗 (BCG) 或单核细胞增生李斯特氏菌）的实验性气源性感染会导致接触 DEP 的啮齿动物肺部细菌负荷增加。 [段落] 我们有新的初步数据表明人类血液吞噬细胞同时吸收 M.tb 和 DEP。在同时添加 DEP 和 M.tb 期间，M.tb 诱导的外周血细胞细胞因子产生以 DEP 剂量依赖性方式发生改变（IFN-γ、TNF-α、IL-6 减少，IL-10 增加）。 M.tb 感染前 20 小时暴露于 DEP 会消除 M.tb 诱导的 IL-6 和 IL-10 产生，这可能表明 DEP 诱导的细胞对后续刺激无反应/耐受的状态，类似于内毒素耐受。我们对健康志愿者吸入 DEP 后进行的独特初步研究表明，M.tb 诱导的 IFN-γ 增加，M.tb 诱导的 IL-6 和 IL-10 释放减少。 DEP 体外添加和体内暴露研究均表明 DEP 降低了血细胞在体外控制 M.tb 生长的能力。 [段落] 本次资助中提出的研究与之前的 DEP (PM) 效应研究在几个重要方面有所不同。将研究 DEP 的影响 (1) 对具有重要公共健康重要性的病原体 (M.tb) 的免疫力，(2) 在有或没有病原体 (M.tb) 特异性记忆免疫的人类中，以及 (3) 体外和体内 DEP 暴露的原代人血细胞。我们建议扩大 DEP 暴露的剂量和时间动力学效应的研究。将评估抗原特异性细胞因子产生、M.tb 诱导的细胞增殖、M.tb 和 Th1 和 Th2 的生长控制以及 Toll 样受体 (TLR) 基因表达及其信号传导途径的变化。 [段落] 我们假设 PM (DEP) 和 M.tb 对人类宿主的综合影响可能会改变抗分枝杆菌免疫反应，从而增加对 M.tb 感染和结核病的易感性，从而对人群水平产生潜在的重要公共卫生影响。公共卫生相关性：空气污染和结核病 (TB) 在全球范围内给肺部健康带来了公共卫生挑战。这笔赠款将解决空气污染物是否会严重改变人体对结核病的防御能力的问题。我们将研究柴油机尾气颗粒和结核病在人体上的结合如何影响人体免疫反应，从而增加结核感染和结核病的脆弱性，这可能会影响人口层面的公共卫生。