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
• 负责人: STEPHAN K SCHWANDER
• 金额: $ 0.96万
• 依托单位: UNIV OF MED/DENT NJ-SCH OF PUBLIC HEALTH
• 依托单位国家: 美国
• 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/8075141
• 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; 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; 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; adaptive immunity; cytokine; dosage; enzyme linked immunospot assay; epidemiologic data; healthy volunteer; human TNF protein; in vivo; killings; macrophage; monocyte; mortality; mycobacterial; novel; particle; particle exposure; pathogen; peripheral blood; pollutant; public health relevance; receptor expression; receptor-mediated signaling; research study; response; transmission process; uptake

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）各自对全球公共卫生，特别是肺部健康构成重大挑战。这项拨款将解决空气污染物是否会严重改变人类抗分枝杆菌免疫力的紧迫问题。城市空气污染是全球发病率和死亡率的主要原因。柴油发动机产生的柴油机排气颗粒（DEP）由各种工业产生，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）生物效应和健康效应的重要模式污染物。越来越多的证据表明，DEP（PM）改变了呼吸道免疫细胞的功能，并增加了对病毒和细菌等感染性病原体的易感性。实验性产气感染细胞内细菌，如结核分枝杆菌（M.tb），卡介苗（BCG）或单核细胞增生李斯特菌导致肺细菌负荷增加暴露于DEP的啮齿动物。我们有新的初步数据表明，人类血液吞噬细胞同时摄取结核分枝杆菌和DEP。在同时添加DEP和结核分枝杆菌期间，结核分枝杆菌诱导的外周血细胞细胞因子产生以DEP剂量依赖性方式改变（IFN-γ、TNF-α、IL-6减少，IL-10增加）。在结核分枝杆菌感染前20小时暴露于DEP可消除结核分枝杆菌诱导的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。我们在健康志愿者中进行的独特的初步研究表明，吸入暴露于DEP后，结核分枝杆菌诱导的IFN-γ增加，结核分枝杆菌诱导的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降低了血细胞体外控制结核分枝杆菌生长的能力。这项资助中提出的研究在几个重要方面与以前的DEP（PM）效应研究不同。将研究DEP的影响：（1）对具有压倒性公共卫生重要性的病原体（结核分枝杆菌）的免疫力，（2）在有和没有病原体（结核分枝杆菌）特异性记忆免疫的人体中，以及（3）在体外和体内暴露于DEP的原代人血细胞中。我们建议扩大我们的研究剂量和时间动力学效应的DEP曝光。将评估抗原特异性细胞因子产生、结核分枝杆菌诱导的细胞增殖、结核分枝杆菌和Th 1和Th 2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。我们假设PM（DEP）和结核分枝杆菌对人类宿主的联合作用可能改变抗分枝杆菌免疫应答，从而增加对结核分枝杆菌感染和结核病的易感性，在人群水平上具有潜在的重要公共卫生影响。空气污染和结核病（TB）在全球范围内对肺部健康构成了公共卫生挑战。这项拨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。我们将研究柴油机尾气颗粒物和结核病对人体的结合如何影响人体免疫反应，从而增加对结核病感染和结核病的脆弱性，这可能会影响人口水平上的公共卫生。