| Summary: | <p>Abstract</p> <p>Background</p> <p>Virulent <it>Mycobacterium leprae </it>interfere with host defense mechanisms such as cytokine activation and apoptosis. The mitochondrial pathway of apoptosis is regulated by the Bcl-2 family of proteins. Expression of Fas ligand and apoptotic proteins is found in leprosy lesions and <it>M. leprae </it>has been shown to activate pro-apoptotic Bcl-2 genes, Bak and Bax. However, the mechanism by which <it>M. leprae </it>modulates apoptosis is as yet unclear. We investigated expression of apoptotic genes in THP-1 monocytes in response to infection by <it>M. leprae </it>and non-pathogenic <it>M. bovis </it>BCG.</p> <p>Results</p> <p><it>M. leprae </it>did not induce apoptosis in THP-1 cells, while BCG induced a significant loss of cell viability by 18 h post-infection at both (multiplicity of infection) MOI-10 and 20, with an increase by 48 h. BCG-induced cell death was accompanied by characteristic apoptotic DNA laddering in cells. Non-viable BCG had a limited effect on host cell death suggesting that BCG-induced apoptosis was a function of mycobacterial viability. <it>M. leprae </it>also activated lower levels of TNF-alpha secretion and TNF-alpha mRNA expression than BCG. <it>Mycobacterium</it>-induced activation of apoptotic gene expression was determined over a time course of infection. <it>M. leprae </it>reduced Bad and Bak mRNA expression by 18 h post-stimulation, with a further decrease at 48 h. Outcome of cell viability is determined by the ratio between pro- and anti-apoptotic proteins present in the cell. <it>M. leprae </it>infection resulted in downregulation of gene expression ratios, Bad/Bcl-2 mRNA by 39% and Bak/Bcl-2 mRNA by 23%. In contrast, live BCG increased Bad/Bcl-2 mRNA (29 %) but had a negligible effect on Bak/Bcl-2 mRNA. Heat killed BCG induced only a negligible (1–4 %) change in mRNA expression of either Bak/Bcl-2 or Bad/Bcl-2. Additionally, <it>M. leprae </it>upregulated the expression of anti-apoptotic gene Mcl-1 while, BCG downregulated Mcl-1 mRNA.</p> <p>Conclusion</p> <p>This study proposes an association between mycobacterium-induced apoptosis in THP-1 cells and the regulation of Bcl-2 family of proteins. <it>M. leprae </it>restricts apoptosis in THP-1 cells by downregulation of Bad and Bak and upregulation of Mcl-1 mRNA expression.</p>
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