Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses againstMycobacterium tuberculosishas been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 μm (PM_2.5) and 10 μm (PM₁₀) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM_2.5or PM₁₀deregulated the ability of the A549 cells to express the antimicrobial peptides human β-defensin 2 (HBD-2) and HBD-3 upon infection withM. tuberculosisand increased intracellularM. tuberculosisgrowth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhancedM. tuberculosisgrowth represent mechanisms by which exposure to air pollution PM may increase the risk ofM. tuberculosisinfection and the development of TB.

Air pollution is one of the leading global public health risks but its magnitude in many developing countries’ cities is not known. We aimed to measure the concentration of particulate matter with aerodynamic diameter <2.5 µm (PM_2.5), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and ozone (O₃) pollutants in two Ugandan cities (Kampala and Jinja). PM_2.5, O₃, temperature and humidity were measured with real-time monitors, while NO₂ and SO₂ were measured with diffusion tubes. We found that the mean concentrations of the air pollutants PM_2.5, NO_2, SO₂ and O₃ were 132.1 μg/m³, 24.9 µg/m³, 3.7 µg/m³ and 11.4 μg/m³, respectively. The mean PM_2.5 concentration is 5.3 times the World Health Organization (WHO) cut-off limits while the NO_2, SO₂ and O₃ concentrations are below WHO cut-off limits. PM_2.5 levels were higher in Kampala than in Jinja (138.6 μg/m³ vs. 99.3 μg/m³) and at industrial than residential sites (152.6 μg/m³ vs. 120.5 μg/m³) but residential sites with unpaved roads also had high PM_2.5 concentrations (152.6 μg/m³). In conclusion, air pollutant concentrations in Kampala and Jinja in Uganda are dangerously high. Long-term studies are needed to characterize air pollution levels during all seasons, to assess related public health impacts, and explore mitigation approaches.

Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications.

Rationale: Associations between urban (outdoor) airborne particulate matter (PM) exposure and TB and potential biological mechanisms are poorly explored.Objectives: To examine whether in vivo exposure to urban outdoor PM in Mexico City and in vitro exposure to urban outdoor PM_2.5(< 2.5 µm median aerodynamic diameter) alters human host immune cell responses toMycobacterium tuberculosis.Methods: Cellular toxicity (flow cytometry, proliferation assay (MTS assay)),M. tuberculosisand PM_2.5phagocytosis (microscopy), cytokine-producing cells (Enzyme-linked immune absorbent spot (ELISPOT)), and signalling pathway markers (western blot) were examined in bronchoalveolar cells (BAC) and peripheral blood mononuclear cells (PBMC) from healthy, non-smoking, residents of Mexico City (n=35; 13 female, 22 male). In vivo-acquired PM burden in alveolar macrophages (AM) was measured by digital image analysis.Measurements and main results: In vitro exposure of AM to PM_2.5did not affectM. tuberculosisphagocytosis. High in vivo-acquired AM PM burden reduced constitutive,M. tuberculosisand PM-induced interleukin-1β production in freshly isolated BAC but not in autologous PBMC while it reduced constitutive production of tumour necrosis factor-alpha in both BAC and PBMC. Further, PM burden was positively correlated with constitutive, PM,M. tuberculosisand purified protein derivative (PPD)-induced interferon gamma (IFN-γ) in BAC, and negatively correlated with PPD-induced IFN-γ in PBMC.Conclusions: Inhalation exposure to urban air pollution PM impairs important components of the protective human lung and systemic immune response againstM. tuberculosis. PM load in AM is correlated with alteredM. tuberculosis-induced cytokine production in the lung and systemic compartments. Chronic PM exposure with high constitutive expression of proinflammatory cytokines results in relative cellular unresponsiveness.

Tuberculosis (TB) and air pollution both contribute significantly to the global burden of disease. Epidemiological studies show that exposure to household and urban air pollution increase the risk of new infections with Mycobacterium tuberculosis (M.tb) and the development of TB in persons infected with M.tb and alter treatment outcomes. There is increasing evidence that particulate matter (PM) exposure weakens protective antimycobacterial host immunity. Mechanisms by which exposure to urban PM may adversely affect M.tb-specific human T cell functions have not been studied. We, therefore, explored the effects of urban air pollution PM_2.5 (aerodynamic diameters ≤2.5µm) on M.tb-specific T cell functions in human peripheral blood mononuclear cells (PBMC). PM_2.5 exposure decreased the capacity of PBMC to control the growth of M.tb and the M.tb-induced expression of CD69, an early surface activation marker expressed on CD3⁺ T cells. PM_2.5 exposure also decreased the production of IFN-γ in CD3⁺, TNF-α in CD3⁺ and CD14⁺ M.tb-infected PBMC, and the M.tb-induced expression of T-box transcription factor TBX21 (T-bet). In contrast, PM_2.5 exposure increased the expression of anti-inflammatory cytokine IL-10 in CD3⁺ and CD14⁺ PBMC. Taken together, PM_2.5 exposure of PBMC prior to infection with M.tb impairs critical antimycobacterial T cell immune functions.