Dysregulation of Apoptosis Is a Risk Factor for Tuberculosis Disease Progression

Background. A major barrier to effective tuberculosis control is our limited understanding of risk factors for tuberculosis disease progression. This study examined the role of apoptosis in immunity to tuberculosis. Methods. Cell subsets from tuberculosis cases and tuberculin skin test-positive (TST+) and TST-negative (TST-) household contacts (HHCs) were analyzed for expression of annexin-V and propidium iodide by flow cytometry. RNA microarrays were used to determine differences in apoptotic gene expression levels and multiplex ligation-dependent probe amplification was used to analyze gene expression in HHCs who progressed to active tuberculosis. Results. T cells from TST+HHC exhibited higher levels of apoptosis than tuberculosis cases; however, tuberculosis cases had a higher proportion of late apoptotic cells within the CD3(+)PD-1(+) subset. Tuberculosis cases had reduced levels of antiapoptotic genes compared to HHCs with a significant reduction in BCL2 associated with disease progression at least 1 year prior to progression. Conclusions. While T cells are clearly able to mount a robust immune response to Mycobacterium tuberculosis, there are increased levels of apoptosis seen in effector T cells from tuberculosis patients. Dysregulation of several apoptotic genes suggest that apoptosis is a major functional pathway that could be targeted for future host-directed therapeutics.