International Journal of Pathogens Review Article
Decoding the Mycobacterium Tuberculosis-Macrophage Interplay: From Immune Defense to Pathogen Persistence
Abstract
Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) and has been responsible for over one billion deaths worldwide over the past two centuries, remaining a major global health challenge despite advances in diagnosis and treatment. The barriers that make tuberculosis difficult to treat and eliminate are inextricably tied to its intracellular habitat. However, a research gap lies in understanding the molecular mechanisms of its survival and host cellular defense against the pathogen. Thus, it is relevant to understand the insights related to the interactions between Mtb effectors and macrophages, the first interacting host cells. In the present review, we highlighted the interactions between Mtb effectors and macrophages. We additionally explored and discussed how Mtb manipulates the defense mechanisms of macrophages to survive and the ability of macrophages to govern and destroy Mtb. The biological processes illustrated in the review explain the control and elimination of Mtb through a variety of mechanisms, including autophagy, apoptosis, inflammasome stimulation, ncRNA activity, phagosomal pH imbalances, and the production of antimicrobial chemicals. However, these difficult conditions reveal Mtb’s limitations in its capacity to manage and make use of them for survival. The discrepancy in Mtb-macrophage crosstalk, where macrophages fail to successfully manage Mtb infection, supported by the expanding discovery of Mtb egress mechanisms, should be the key problem in TB control. These insights offer important clues related to the pathways and events providing information essential for TB diagnosis, treatment and prevention.
Keywords
References (1)
- Graves DT, Milovanova TN. Mucosal immunity and the FOXO1 transcription factors. Frontiers in immunology. 2019 Nov 29;10:2530. 2. Hou F, Xiao K, Tang L, Xie L. Diversity of macrophages in lung homeostasis and diseases. Frontiers in immunology. 2021 Sep 24;12:753940. 3. Bose Dasgupta S, Pieters J. Macrophage-microbe interaction: Lessons learned from the pathogen Mycobacterium tuberculosis. Semin Immunopathol. 2018;40(6):577–591. 4. Flentie K, Garner AL, Stallings CL. Mycobacterium tuberculosis transcription machinery: Ready to respond to host attacks. J Bacteriol. 2016;198(9):1360–1373. 5. Fu LM, Fu-Liu CS. Is Mycobacterium tuberculosis a closer relative to Gram-positive or Gram-negative bacterial pathogens? Tuberculosis. 2002;82(2–3):85–90. 6. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393(6685):537–544. 7. Vergne I, Gilleron M, Nigou J. Manipulation of the endocytic pathway and phagocyte functions by Mycobacterium tuberculosis lipoarabinomannan. Front Cell Infect Microbiol. 2015;4:187. 8. Stamm CE, Collins AC, Shiloh MU. Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol Rev. 2015;264(1):204–219. 9. Songane M, Kleinnijenhuis J, Netea MG, Van Crevel R. The role of autophagy in host defence against Mycobacterium tuberculosis infection. Tuberculosis. 2012;92(5):388–396. 10. Su H, Zhu S, Luo R, Li Z, Li H, Zhu L, et al. Mycobacterium tuberculosis hijacks host macrophages-derived interleukin 16 to block phagolysosome maturation for enhancing intracellular growth. Emerg Microbes Infect. 2024;13(1):2302152. 11. Liu D, Wang J, Xu Z, Chen X, Jiao X. Phagocytosis: Strategies for macrophages to hunt Mycobacterium tuberculosis. One Health Adv. 2024;2(1):27. 12. Kim TS, Jin YB, Kim YS, Kim S, Kim JK, Lee HM, et al. SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions. Autophagy. 2019;15(8):1356–1375. 13. Paik S, Jo EK. An interplay between autophagy and immunometabolism for host defense against mycobacterial infection. Frontiers in immunology. 2020 Nov 12;11:603951. 14. Arnett E, Schlesinger LS. Live and let die: TB control by enhancing apoptosis. Immunity. 2021;54(8):1625–1627. 15. Stutz MD, Clark MP, Doerflinger M, Pellegrini M. Macrophage and neutrophil death programs differentially confer resistance to tuberculosis. Immunity. 2021;54(8):1758–1771. 16. Vu A, Nguyen T, Kim BJ, Nguyen AD. Host cell death and modulation of immune response against Mycobacterium tuberculosis infection. Int J Mol Sci. 2024;25(11):6255. 17. Yang Q, Shi C, Yang L, Liu Y, Guo X, Zhang Y, et al. CD157 confers host resistance to Mycobacterium tuberculosis via TLR2-CD157-PKCzeta-induced reactive oxygen species production. mBio. 2019;10(4):e01696–19. 18. Shi X, Li Y, Ran J, Zhang J, Huang X, Xu J, et al. Mycobacterium tuberculosis Rv1324 protein contributes to mycobacterial persistence and causes pathological lung injury in mice by inducing ferroptosis. Microbiol Spectr. 2023;11(1):e0382022. 19. Mishra BB, Moura-Alves P, Sonawane A, Hacohen N, Griffiths G, Moita LF, et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cell Microbiol. 2010;12(8):1046–1063. 20. Dorhoi A, Kaufmann SHE. Perspectives on host adaptation in response to Mycobacterium International Journal of Pathogens Volume 3, Issue 2 ISSN: 3048-829X © STM Journals 2026. All Rights Reserved 69 tuberculosis: Modulation of inflammation. Semin Immunol. 2014;26(6):533–542. 21. Saiga H, Kitada S, Shimada Y, Kamiyama N, Okuyama M, Makino M, et al. Critical role of AIM2 in Mycobacterium tuberculosis infection. Int Immunol. 2012;24(10):637–644. 22. Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20(3):143–157. 23. Beckwith KS, Beckwith MS, Ullmann S, Saetra RS, Kim H, Marstad A, et al. Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection. Nat Commun. 2020;11(1):2270. 24. Shi Q, Wang J, Yang Z, Liu Y. CircAGFG1 modulates autophagy and apoptosis of macrophages infected by Mycobacterium tuberculosis via the Notch signaling pathway. Ann Transl Med. 2020;8(10):645. 25. Li D, Gao C, Zhao L, Zhang Y. Inflammatory response is modulated by lincRNACox2 via the NF-kappaB pathway in macrophages infected by Mycobacterium tuberculosis. Mol Med Rep. 2020;22(1):145–154. 26. Li M, Wang Y, Zhu J, Zhao L, Liu Y, Liu Z, et al. Long non-coding PCED1B-AS1 regulates macrophage apoptosis and autophagy by sponging miR-155 in active tuberculosis. Biochem Biophys Res Commun. 2019;509(3):803–809. 27. Jiang F, Lou J, Zheng XM, Yang XY. LncRNA MIAT regulates autophagy and apoptosis of macrophage infected by Mycobacterium tuberculosis through the miR-665/ULK1 signaling axis. Molecular immunology. 2021 Nov 1;139:42-9. 28. Vijayaraghavan M, Gadad SS, Dhandayuthapani S. Long non-coding RNA transcripts in Mycobacterium tuberculosis-host interactions. Non-coding RNA Research. 2025 Apr 1;11:281-93. 29. Ke Z, Lu J, Zhu J, Yang Z, Jin Z, Yuan L. Down-regulation of lincRNA-EPS regulates apoptosis and autophagy in BCG-infected RAW264. 7 macrophages via JNK/MAPK signaling pathway. Infection, Genetics and Evolution. 2020 Jan 1;77:104077. 30. Orecchioni M, Ghosheh Y, Pramod AB, Ley K. Macrophage polarization: different gene signatures in M1 (LPS+) vs. classically and M2 (LPS–) vs. alternatively activated macrophages. Frontiers in immunology. 2019 May 24;10:1084. 31. Bo H, Moure UA, Yang Y, Pan J, Li L, Wang M, Ke X, Cui H. Mycobacterium tuberculosis-macrophage interaction: Molecular updates. Frontiers in Cellular and Infection Microbiology. 2023 Mar 3;13:1062963. 32. Russell DG, Huang L, VanderVen BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19(5):291–304. 33. Gleeson LE, Sheedy FJ. Metabolic reprogramming and inflammation: Fuelling the host response to pathogens. Semin Immunol. 2016;28(5):450–468. 34. Pisu D, Huang L, Grenier JK, Russell DG. Dual RNA-seq of Mtb-infected macrophages in vivo reveals ontologically distinct host-pathogen interactions. Cell Rep. 2020;30(2):335–350. 35. Van Den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: Where are we (going)? Trends Immunol. 2017;38(6):395–406. 36. Guo Q, Bi J, Li M, Ge W, Xu Y, Fan W, Wang H, Zhang X. ESX secretion-associated protein C from Mycobacterium tuberculosis induces macrophage activation through the Toll-like receptor-4/mitogen-activated protein kinase signaling pathway. Frontiers in cellular and infection microbiology. 2019 May 10;9:158. 37. Nasiri MJ, Venketaraman V. Advances in host-pathogen interactions in tuberculosis: Emerging strategies for therapeutic intervention. Int J Mol Sci. 2025;26(4):1621. 38. Alsayed SSR, Gunosewoyo H. Combating tuberculosis via restoring the host immune capacity by targeting M. tb kinases and phosphatases. Int J Mol Sci. 2024;25(22):12481. 39. Bao C, Zhang Y, Feng J, Hong X, Gao N, Feng G. Deciphering tuberculosis: lysosome-centric insights into pathogenesis and therapies. Frontiers in cellular and infection microbiology. 2025 May 14;15:1582037. 40. Xander C, Rajagopalan S, Jacobs WR, Braunstein M. The SapM phosphatase can arrest phagosome maturation in an ESX-1 independent manner in Mycobacterium tuberculosis and BCG. Infect Immun. 2024;92(7):e0021724. Decoding the Mycobacterium Tuberculosis-Macrophage Interplay Jain and Debroy © STM Journals 2026. All Rights Reserved 70 41. Nagdev PK, Agnivesh PK, Roy A, Sau S, Kalia NP. Exploring and exploiting the host cell autophagy during Mycobacterium tuberculosis infection. Eur J Clin Microbiol Infect Dis. 2023;42(11):1297–1315. 42. Abdalla AE, Lambert N, Deng Q, Xie J. Intelligent mechanisms of macrophage apoptosis subversion by Mycobacterium. Pathogens. 2020;9(3):218. 43. Zhuang L, Yang L, Li L, Ye Z, Gong W. Mycobacterium tuberculosis: Immune response, biomarkers, and therapeutic intervention. MedComm. 2024;5(1):e419. 44. Park EJ, Kim I, Jo EK. Host immune pathways to Mycobacterium tuberculosis infection. J Bacteriol Virol. 2024;54(3):167–190. 45. Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, et al. Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe. 2015;17(6):799–810. 46. Jayakumar D, Jacobs WR, Narayanan S. Protein kinase E of Mycobacterium tuberculosis has a role in the nitric oxide stress response and apoptosis in a human macrophage model of infection. Cell Microbiol. 2008;10(2):365–374. 47. Chen Y, MacGilvary NJ, Tan S. Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator. PLoS Genet. 2024;20(1):e1011143. 48. Gautam US, Sikri K, Vashist A, Singh V, Tyagi JS. Mycobacterium tuberculosis sensor kinase DosS modulates the autophagosome in a DosR-independent manner. Commun Biol. 2019;2(1):349. 49. Kurthkoti K, Amin H, Marakalala MJ, Ghanny S, Subbian S, Sakatos A, et al. The capacity of Mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron-deprived microenvironments of human granulomas. mBio. 2017;8(4):e01092–17. 50. Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. Host-directed therapies for bacterial and viral infections. Nat Rev Drug Discov. 2018;17(1):35–56. 51. Wallis RS, Hafner R. Advancing host-directed therapy for tuberculosis. Nat Rev Immunol. 2015;15(4):255–263. 52. Singhal A, Jie L, Kumar P, Hong GS, Leow MKS, Paleja B, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014;6(263):263ra159. 53. Lachmandas E, Eckold C, Bohme J, Koeken VACM, Marzuki M, Blok BA, et al. Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. J Infect Dis. 2019;220(1):139–150. 54. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–1773. 55. Fabri M, Stenger S, Shin DM, Yuk JM, Liu PT, Realegeno S, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med. 2011;3(104):104ra102. 56. Tahir F, Bin Arif T, Ahmed J, Shah SR, Khalid M. Anti-tuberculous effects of statin therapy: A review of literature. Cureus. 2020;12(3):e7395. 57. Dutta NK, Bruiners N, Pinn ML, Zimmerman MD, Prideaux B, Dartois V, et al. Statin adjunctive therapy shortens the duration of TB treatment in mice. J Antimicrob Chemother. 2016;71(6):1570–1577. 58. Vijayaraghavan M, Gadad SS, Dhandayuthapani S. Long non-coding RNA transcripts in Mycobacterium tuberculosis-host interactions. Non-coding RNA Research. 2025 Apr 1;11:281-93