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theses

Tuberculosis (TB) and air pollution both contribute significantly to the global burden of disease. Epidemiological studies provide evidence that indoor (household) air pollution increases the risk of new infections with Mycobacterium tuberculosis (M.tb) and development of TB. The mechanisms by which exposure to ‘real-world’-derived urban ambient (outdoor) particulate matter (PM) adversely affects M.tb-specific human host T cell functions in vitro have not been studied. In this thesis research, we explored the effects of air pollution PM2.5 (≤2.5 µm, median aerodynamic diameter) collected in the Iztapalapa municipality of Mexico City on M.tb-specific T cell functions in human peripheral blood mononuclear cells (PBMC). Upon in vitro exposure, PM2.5 was observed in clusters of free, non-membrane-bound particle agglomerates in the cytoplasm of the exposed cells. PM2.5 exposure did not alter the expression of activation marker CD54 on antigen presenting cells (APC), however, increased the expression of CD80 while decreasing the constitutively expressed CD86 on monocytes during M.tb infection. Exposure to PM2.5 of M.tb-infected PBMC led to an increase of intracellular growth of M.tb, indicating loss of M.tb growth controlling capacity of the cells that occurred independent of PM-induced changes to PBMC viability. Exposure of PBMC to PM2.5 also altered M.tb-specific T-cell immune responses by (1) decreasing the surface expression of early T cell activation markers CD69 and CD25 on T cells, (2) inhibiting the intracellular expression of both interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and (3) decreasing the expression of T-box transcription factor TBX21 (T-bet) known to directly regulate the expression of IFN-γ. In contrast, PM2.5 exposure increased the intracellular expression of the anti-inflammatory cytokine interleukin 10 (IL-10) and the phosphorylation of transcription factor STAT-3. The observed PM2.5-induced decrease in the expression of human pro-inflammatory M.tb-specific T cell cytokines, and the loss of intracellular M.tb growth control are associated with the increased expression of anti-inflammatory cytokine IL-10 and decreased expression of transcription factor T-bet. Together, the findings of this study suggest that the PM2.5-induced decrease of critical human host immune cell functions against M.tb represents the mechanistic correlate of epidemiological observations that outdoor air pollution exposure is associated with increases in the incidence of TB and with adversely modified TB treatment outcomes.

ETD_9439

Ph.D.

Includes bibliographical references

by Olufunmilola Ibironke

doi:10.7282/t3-v8cf-k196

ETD doctoral

The author owns the copyright to this work.