Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis

描述(申请人提供)：空气污染和结核病(结核病)都是对全球公共卫生，特别是对肺部健康的重大挑战。这笔赠款将解决一个紧迫的问题，即空气污染物是否会显著改变人类的抗分枝杆菌免疫能力。[段落]城市空气污染在很大程度上导致全世界的发病率和死亡率。柴油机排放的柴油机尾气颗粒物(DEP)由各行各业产生，占大城市可吸入颗粒物的40%，并在地下矿山积累。DEP是研究可吸入颗粒物(PM)对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)改变了呼吸道免疫细胞的功能，增加了对病毒和细菌等传染性病原体的易感性。实验性产气性感染细胞内细菌，如结核分枝杆菌(M.tb)、卡介苗(BCG)或单核细胞增生性李斯特菌(Listeria Moncedrosis)会导致暴露于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摄取结核分枝杆菌和DEP。在同时加入DEP和M.tb的过程中，M.tb诱导的外周血细胞因子的产生以DEP剂量依赖的方式发生改变(干扰素-γ、肿瘤坏死因子-α、IL-6降低，IL-10升高)。在结核分枝杆菌感染前20小时暴露于DEP可抑制结核分枝杆菌诱导的IL-6和IL-10的产生，这可能表明DEP诱导的细胞对随后的刺激无反应/耐受，类似于内毒素耐受。我们对健康志愿者吸入DEP后的独特初步研究显示，结核分枝杆菌诱导的干扰素-γ增加，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降低了血细胞在体外控制结核分枝杆菌生长的能力。[段落]这笔赠款中的拟议研究在几个重要方面与以前的环境保护(PM)效应研究有所不同。将研究(1)对一种具有压倒公众健康重要性的病原体(M.tb)的免疫力，(2)具有和不具有病原体(M.tb)特异性记忆免疫力的人类，以及(3)在体外和体内暴露于DEP的原代人类血细胞。我们建议扩大我们对DEP暴露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的产生、结核分枝杆菌诱导的细胞增殖、结核分枝杆菌和Th1、Th2的生长控制以及Toll样受体(Toll Like Receptor，TLR)基因及其信号通路的变化。[段落]我们假设PM(DEP)和M.tb对人类宿主的联合作用可能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，在人群水平上具有潜在的重要公共卫生影响。公共卫生相关性：空气污染和结核病在全球范围内对肺部健康构成公共卫生挑战。这笔赠款将解决空气污染物是否会严重改变人类对结核病的身体防御能力。我们将研究柴油废气微粒和人体上的结核病的结合如何影响人体的免疫反应，从而增加对结核病感染和结核病的易感性，这可能在人口水平上影响公众健康。

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.