Air Pollution Particle Effects on Human Antimycobacterial Immunity

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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.