Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis

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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.