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.