Journal List > J Bacteriol Virol > v.46(4) > 1034239

J Bacteriol Virol. 2016 Dec;46(4):312-318. Korean.
Published online December 31, 2016.
Copyright © 2016 The Korean Society for Microbiology and The Korean Society of Virology
Apoptotic Effect of Macrophages against Mycobacterium tuberculosis
Lee-Han Kim and Sung Jae Shin
Department of Microbiology, Institute of Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Corresponding author: Sung Jae Shin. Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Phone: +82-2-2228-1813, Fax: +82-2-392-9310, Email:
Received December 09, 2016; Revised December 09, 2016; Accepted December 09, 2016.

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (


Mycobacterium tuberculosis (Mtb) causing tuberculosis as an intracellular pathogen initially infects alveolar macrophages following aerosol inhalation. Thus, macrophages play a critical role in the establishment of Mtb infection and macrophage cell death, a common outcome during Mtb infection, may initiate host- or pathogen-favored immune responses, resulting in facilitating protection or pathogenesis, respectively. In addition, virulent Mtb strains are known to inhibit apoptosis and consequently down-regulates immune response using a variety of strategies. In many recent studies have shown that virulent Mtb can either augment or reduce apoptosis by regulating expression of pro-apoptotic and anti-apoptotic proteins belonging to Bcl-2 family proteins. In this review, we will discuss and dissect the apoptotic pathways of Bcl-2 family proteins in Mtb-infected macrophages.

Keywords: Mycobacterium tuberculosis; Apoptosis; Bcl-2 family proteins; Anti-apoptotic proteins; Pro-apoptotic proteins


Figure 1
Regulation of apoptosis signaling pathway by Bcl-2 family proteins. The mitochondrial outer membrane permeabilization (MOMP) can be regulated by either extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) pathways. MOMP triggers the release of apoptogenic factor such as cytochrome c into cytosol to facilitate activation of caspase 3, resulting in induction of apoptosis. Virulent Mtb promotes the induction and production of Bcl-2 family proteins (①) and eventually inhibits apoptosis pathways (②) to multiplicate inside macrophages. FADD; Fas-associated death domain, Bax; Bcl-2-associated X protein, Bak; Bcl-2-antagonist killer, (t)Bid; (truncated) Bax-like BH3 protein, DISC; Death inducing signaling complex, Apaf1; Apoptotic protease activating factor 1, Mtb; Mycobacterium tuberculosis
Click for larger image


This study was supported by the Basic Science Research Program and the International Research & Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning of Korea (NRF-2016R1A2A1A05005263 and NRF-2014K1A3A7A03075054).

1. Wipperman MF, Sampson NS, Thomas ST. Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis. Crit Rev Biochem Mol Biol 2014;49:269–293.
2. Chen M, Divangahi M, Gan H, Shin DS, Hong S, Lee DM, et al. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 2008;205:2791–2801.
3. Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan HX, et al. Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. Mucosal Immunol 2011;4:279–287.
4. Abebe M, Kim L, Rook G, Aseffa A, Wassie L, Zewdie M, et al. Modulation of cell death by M. tuberculosis as a strategy for pathogen survival. Clin Dev Immunol 2011;2011:678570.
5. Chen M, Gan H, Remold HG. A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 2006;176:3707–3716.
6. Fortune SM, Solache A, Jaeger A, Hill PJ, Belisle JT, Bloom BR, et al. Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 2004;172:6272–6280.
7. Gehring AJ, Dobos KM, Belisle JT, Harding CV, Boom WH. Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing. J Immunol 2004;173:2660–2668.
8. Parandhaman DK, Narayanan S. Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection. Front Cell Infect Microbiol 2014;4:31.
9. Fenton MJ, Vermeulen MW. Immunopathology of tuberculosis: roles of macrophages and monocytes. Infect Immun 1996;64:683–690.
10. Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR. Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J Immunol 2003;170:430–437.
11. Pedruzzi G, Das PN, Rao KV, Chatterjee S. Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model. J Theor Biol 2016;389:159–170.
12. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35:495–516.
13. Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000;69:217–245.
14. Aguiló N, Uranga S, Marinova D, Martin C, Pardo J. Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis. Cell Death Dis 2014;5:e1343.
15. Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev 2003;193:10–21.
16. Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007;8:405–413.
17. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9:47–59.
18. Lee J, Hartman M, Kornfeld H. Macrophage apoptosis in tuberculosis. Yonsei Med J 2009;50:1–11.
19. Green DR, Galluzzi L, Kroemer G. Cell biology. Metabolic control of cell death. Science 2014;345:1250256.
20. Halder P, Kumar R, Jana K, Chakraborty S, Ghosh Z, Kundu M, et al. Gene expression profiling of Mycobacterium tuberculosis Lipoarabinomannan-treated macrophages: A role of the Bcl-2 family member A1 in inhibition of apoptosis in mycobacteria-infected macrophages. IUBMB Life 2015;67:726–736.
21. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005;73:1907–1916.
22. Navarre WW, Zychlinsky A. Pathogen-induced apoptosis of macrophages: a common end for different pathogenic strategies. Cell Microbiol 2000;2:265–273.
23. Fratazzi C, Arbeit RD, Carini C, Balcewicz-Sablinska MK, Keane J, Kornfeld H, et al. Macrophage apoptosis in mycobacterial infections. J Leukoc Biol 1999;66:763–764.
24. Keane J, Remold HG, Kornfeld H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol 2000;164:2016–2020.
25. Gan H, Lee J, Ren F, Chen M, Kornfeld H, Remold HG. Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence. Nat Immunol 2008;9:1189.
26. McGarvey JA, Wagner D, Bermudez LE. Differential gene expression in mononuclear phagocytes infected with pathogenic and non-pathogenic mycobacteria. Clin Exp Immunol 2004;136:490–500.
27. Rengarajan J, Bloom BR, Rubin EJ. Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc Natl Acad Sci U S A 2005;102:8327–8332.
28. Velmurugan K, Chen B, Miller JL, Azogue S, Gurses S, Hsu T, et al. Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells. PLoS Pathog 2007;3:e110.
29. Aguilo JI, Alonso H, Uranga S, Marinova D, Arbués A, de Martino A, et al. ESX-1-induced apoptosis is involved in cell-to-cell spread of Mycobacterium tuberculosis. Cell Microbiol 2013;15:1994–2005.
30. Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 2000;7:1182–1191.
31. Garry RF. Extensive antigenic mimicry by retrovirus capsid proteins. AIDS Res Hum Retroviruses 1990;6:1361–1362.
32. Zhou W, Hu J, Tang H, Wang D, Huang X, He C, et al. Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors. BMC Cancer 2011;11:485.
33. Mogga SJ, Mustafa T, Sviland L, Nilsen R. Increased Bcl-2 and reduced Bax expression in infected macrophages in slowly progressive primary murine Mycobacterium tuberculosis infection. Scand J Immunol 2002;56:383–391.
34. Sohn H, Lee KS, Kim SY, Shin DM, Shin SJ, Jo EK, et al. Induction of cell death in human macrophages by a highly virulent Korean Isolate of Mycobacterium tuberculosis and the virulent strain H37Rv. Scand J Immunol 2009;69:43–50.
35. Wang FY, Wang XM, Wang C, Wang XF, Zhang YQ, Wu JD, et al. Suppression of Mcl-1 induces apoptosis in mouse peritoneal macrophages infected with Mycobacterium tuberculosis. Microbiol Immunol 2016;60:215–227.
36. Haoues M, Refai A, Mallavialle A, Barbouche MR, Laabidi N, Deckert M, et al. Forkhead box O3 (FOXO3) transcription factor mediates apoptosis in BCG-infected macrophages. Cell Microbiol 2014;16:1378–1390.