Host-Pathogen Interactions in Mycobacterium tuberculosis: From Phagosome Arrest to Granuloma Dynamics- A review
DOI:
https://doi.org/10.67601/njbls.v3i2a.47Keywords:
Macrophage, Latency, Persistence, Granuloma, Drug tolerance, Host-directed therapyAbstract
Mycobacterium tuberculosis (Mtb) remains one of the leading causes of death from a single infectious agent despite effective antimicrobial therapy. Its success is largely attributed to its ability to survive within host macrophages, evade immune clearance, establish latent infection, and develop phenotypic drug tolerance, complicating disease control and treatment. Although these mechanisms have been widely studied, their interrelationship remains incompletely understood. This mini narrative review examines five key aspects of Mtb pathogenesis: macrophage survival, inhibition of phagosome–lysosome fusion, granuloma formation, latent versus active tuberculosis, and drug tolerance. A literature search was conducted using PubMed, Web of Science, Google Scholar, and Scopus with relevant keywords and Boolean operators. Articles published predominantly between 2016 and 2026 were included. The findings indicate that Mtb manipulates macrophage antimicrobial functions, inhibits phagosome maturation and lysosomal fusion, promotes granuloma formation that both restricts and protects bacilli, transitions between latent and active disease in response to host and environmental factors, and develops drug-tolerant persister populations that contribute to prolonged treatment and relapse. Together, these interconnected mechanisms enable long-term bacterial persistence and immune evasion. Understanding these dynamic host–pathogen interactions is essential for developing integrated diagnostic, therapeutic, and host-directed strategies to improve tuberculosis control.
References
Abel, L., Fellay, J., Haas, D. W., Schurr, E., Srikrishna, G., Urbanowski, M., Chaturvedi, N., Srinivasan, S., Johnson, D. H., & Bishai, W. R. (2018). Genetics of human susceptibility to active and latent tuberculosis: Present knowledge and future perspectives. The Lancet Infectious Diseases, 18(3), e64–e75. https://doi.org/10.1016/S1473-3099(17)30623-0
Adane, G., Lemma, M., Geremew, D., Sisay, T., Tessema, M. K., Damtie, D., & Ayelign, B. (2021). Genetic polymorphism of tumor necrosis factor-alpha, interferon-gamma and interleukin-10 and association with risk of Mycobacterium tuberculosis infection. Journal of Evidence-Based Integrative Medicine, 26, 2515690X211006344. https://doi.org/10.1177/2515690X211006344
Aravindan, P. P. (2019). Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India, 36(3), 244–252. https://doi.org/10.4103/lungindia.lungindia_146_15
Bao, C., Zhang, Y., Feng, J., Hong, X., Gao, N., & Feng, G. (2025). Deciphering tuberculosis: Lysosome-centric insights into pathogenesis and therapies. Frontiers in Cellular and Infection Microbiology, 15, 1582037. https://doi.org/10.3389/fcimb.2025.1582037
Bi, K., (2022). The past, present and future of tuberculosis treatment. Zhejiang Da Xue Xue Bao Yi Xue Ban, 51(4), 499–511. https://doi.org/10.3724/zdxbyxb-2022-0454
Biyikli, O. O., Baysak, A., Ece, G., Oz, A. T., Ozhan, M. H., & Berdeli, A. (2016). Role of Toll-like receptors in tuberculosis infection. Archives of Clinical Infectious Diseases, 11(4), e20224. https://doi.org/10.5812/jjm.20224
Bo, H., Moure, U. A. E., Yang, Y., Pan, J., Li, L., Wang, M., Ke, X., & Cui, H. (2023). Mycobacterium tuberculosis-macrophage interaction: Molecular updates. Frontiers in Cellular and Infection Microbiology, 13, 1062963. https://doi.org/10.3389/fcimb.2023.1062963
Cadena, A. M., Flynn, J. L., & Fortune, S. M. (2016). The importance of first impressions: Early events in Mycobacterium tuberculosis infection influence outcome. mBio, 7(2), e00342-16. https://doi.org/10.1128/mBio.00342-16
Cai, L., Li, Z., Guan, X., Cai, K., Wang, L., Liu, J., & Tong, Y. (2019). The research progress of host genes and tuberculosis susceptibility. Oxidative Medicine and Cellular Longevity, 2019, 9273056. https://doi.org/10.1155/2019/9273056
Cambier, C. J., Falkow, S., & Ramakrishnan, L. (2018). Host evasion and exploitation schemes of Mycobacterium tuberculosis. Pathogens and Disease, 76(4), fty037. https://doi.org/10.1093/femspd/fty037
Carranza, C., & Chavez-Galan, L. (2019). Several routes to the same destination: Inhibition of phagosome-lysosome fusion by Mycobacterium tuberculosis. The American Journal of the Medical Sciences, 357(3), 184–194. https://doi.org/10.1016/j.amjms.2018.12.007
Carranza, C., Pedraza-Sanchez, S., de Oyarzabal-Mendez, E., & Torres, M. (2020). Diagnosis for latent tuberculosis infection: New alternatives. Frontiers in Immunology, 11, 2006. https://doi.org/10.3389/fimmu.2020.02006
Chandra, P., Grigsby, S. J., Philips, J. A., & Ernst, J. D. (2022). Immune evasion and provocation by Mycobacterium tuberculosis. Nature Reviews Microbiology, 20(12), 750–766. https://doi.org/10.1038/s41579-022-00763-4
Chirakos, A. E., Balaram, A., Conrad, W., & Champion, P. A. (2020). Modeling tubercular ESX-1 secretion using Mycobacterium marinum. Microbiology and Molecular Biology Reviews, 84(4), e00082-19. https://doi.org/10.1128/MMBR.00082-19
Cohen, S. B., Gern, B. H., & Urdahl, K. B. (2022). The tuberculous granuloma and preexisting immunity. Annual Review of Immunology, 40, 589–614. https://doi.org/10.1146/annurev-immunol-093019-125148
Cronan, M. R. (2022). In the thick of it: Formation of the tuberculous granuloma and its effects on host and therapeutic responses. Frontiers in Immunology, 13, 820134. https://doi.org/10.3389/fimmu.2022.820134
Datta, D., Jamwal, S., Jyoti, N., Patnaik, S., & Kumar, D. (2024). Actionable mechanisms of drug tolerance and resistance in Mycobacterium tuberculosis. The FEBS Journal, 291(20), 4433–4452. https://doi.org/10.1111/febs.17126
Drain, P. K., Bajema, K. L., Dowdy, D., Dheda, K., Naidoo, K., Schumacher, S. G., Ma, S., Meermeier, E., Lewinsohn, D. M., & Sherman, D. R. (2018). Incipient and subclinical tuberculosis: A clinical review of early stages and progression of infection. Clinical Microbiology Reviews, 31(4), e00021-18. https://doi.org/10.1128/CMR.00021-18
Ehrt, S., Schnappinger, D., & Rhee, K. Y. (2018). Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis. Nature Reviews Microbiology, 16(8), 496–507. https://doi.org/10.1038/s41579-018-0013-4
Flynn, J. L., & Chan, J. (2022). Immune cell interactions in tuberculosis. Cell, 185(25), 4682–4702. https://doi.org/10.1016/j.cell.2022.10.025
Ghazaei, C. (2018). Mycobacterium tuberculosis and lipids: Insights into molecular mechanisms from persistence to virulence. Journal of Research in Medical Sciences, 23(1), 63. https://doi.org/10.4103/jrms.JRMS_904_17
Glaziou, P., Floyd, K., & Raviglione, M. C. (2018). Global epidemiology of tuberculosis. Seminars in Respiratory and Critical Care Medicine, 39(3), 271–285. https://doi.org/10.1055/s-0038-1651492
Goossens, S. N., Sampson, S. L., & Van Rie, A. (2020). Mechanisms of drug-induced tolerance in Mycobacterium tuberculosis. Clinical Microbiology Reviews, 34(1), e00141-19. https://doi.org/10.1128/CMR.00141-20
Gunasekaran, H., Ranganathan, U. D., & Bethunaickan, R. (2025). The importance of inflammatory biomarkers in detecting and managing latent tuberculosis infection. Frontiers in Immunology, 16, 1538127. https://doi.org/10.3389/fimmu.2025.1538127
Huang, L., Nazarova, E. V., Tan, S., Liu, Y., & Russell, D. G. (2018). Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny. Journal of Experimental Medicine, 215(4), 1135–1152. https://doi.org/10.1084/jem.20172020
Jaiswal, S., Fatima, S., Velarde de la Cruz, E., & Kumar, S. (2025). Unraveling the role of the immune landscape in tuberculosis granuloma. Tuberculosis, 152, 102615. https://doi.org/10.1016/j.tube.2025.102615
Jeong, E.-K., Kim, Y., Kim, J., & Shin, S.-J. (2022). Host-directed therapies for tuberculosis. Pathogens, 11(11), 1291. https://doi.org/10.3390/pathogens11111291
Jiao, L., - (2022). Genetic architecture of tuberculosis susceptibility: A comprehensive research synopsis, meta-analyses, and epidemiological evidence. Infection, Genetics and Evolution, 106, 105379. https://doi.org/10.1016/j.meegid.2022.105379
Krasilnikov, I., Lehnherr-Ilyina, T., Djonovic, M., Artamonova, I., Nikitin, M., & Kislichkin, N. (2024). Cracking the antigenic code of mycobacteria: CFP-10/ESAT-6 tuberculosis skin test and misleading results. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 36, 100436. https://doi.org/10.1016/j.jctube.2024.100436
Krishnan, V., Nath, S., Nair, P., & Das, B. (2023). Mycobacterium tuberculosis and its clever approaches to escape the deadly macrophage. World Journal of Microbiology and Biotechnology, 39(11), 300. https://doi.org/10.1007/s11274-023-03768-0
Krueger, G., Faisal, S., & Dorhoi, A. (2025). Microenvironments of tuberculous granuloma: Advances and opportunities for therapy. Frontiers in Immunology, 16, 1575133. https://doi.org/10.3389/fimmu.2025.1575133
Lei, Y., Zhang, Y., Zhang, H., - (2023). Epinephrine stimulates Mycobacterium tuberculosis growth and biofilm formation. International Journal of Molecular Sciences, 24(8), 7474. https://doi.org/10.3390/ijms24087474
Li, Y., - (2021). Ribosome hibernation: A new molecular framework for targeting nonreplicating persisters of mycobacteria. Microbiology, 167(2), 001017. https://doi.org/10.1099/mic.0.001017
Liebenberg, D., - (2022). Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management. Frontiers in Cellular and Infection Microbiology, 12, 943545. https://doi.org/10.3389/fcimb.2022.943545
Liu, S., Guan, L., Peng, C., Cheng, Y., Cheng, H., Wang, F., Ma, M., Zheng, R., Ji, Z., Cui, P., Ren, Y., Li, L., Shi, C., Wang, J., Huang, X., Cai, X., Qu, D., Zhang, H., Mao, Z., ... Ge, B. (2023). Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival. Cell Host & Microbe, 31(11), 1820–1836.e10. https://doi.org/10.1016/j.chom.2023.10.006
Liu, Y., Li, H., Dai, D., He, J., & Liang, Z. (2024). Gene regulatory mechanism of Mycobacterium tuberculosis during dormancy. Current Issues in Molecular Biology, 46(6), 5825–5844. https://doi.org/10.3390/cimb46060349
Liu, Y., Tan, S., Huang, L., Abramovitch, R. B., Rohde, K. H., Zimmerman, M. D., Chen, C., Dartois, V., VanderVen, B. C., & Russell, D. G. (2016). Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. Journal of Experimental Medicine, 213(5), 809–825. https://doi.org/10.1084/jem.20151248
Lyu, J., Narum, D. E., Baldwin, S. L., Larsen, S. E., Bai, X., Griffith, D. E., Dartois, V., Naidoo, T., Steyn, A. J. C., Coler, R. N., & Chan, E. D. (2024). Understanding the development of tuberculous granulomas: Insights into host protection and pathogenesis, a review in humans and animals. Frontiers in Immunology, 15, 1427559. https://doi.org/10.3389/fimmu.2024.1427559
McCaffrey, E. F., Delmastro, A. C., Fitzhugh, I., Ranek, J. S., Douglas, S., Peters, J. M., Camacho Fullaway, C., Bosse, M., Liu, C. C., Gillen, C., Greenwald, N. F., Anzick, S., Martens, C., Winfree, S., Bai, Y., Sowers, C., Goldston, M., Kong, A., Boonrat, P., ... Angelo, M. (2026). The immunometabolic topography of cellular organization and bacterial control in tuberculosis granulomas. Nature Immunology, 27(4), 867–880. https://doi.org/10.1101/2025.02.18.638923
Mehta, M., & Singh, A. (2019). Mycobacterium tuberculosis WhiB3 maintains redox homeostasis and survival in response to reactive oxygen and nitrogen species. Free Radical Biology and Medicine, 131, 50–58. https://doi.org/10.1016/j.freeradbiomed.2018.11.019
Meng, C., Chen, G., Wen, D., Dong, L., Cui, X., Jing, X., Cui, J., Gao, Y., Liu, Y., Bu, H., & Wu, C. (2023). The expression of Nramp1 modulates the uptake of Mycobacterium tuberculosis by macrophages through alternating inflammatory responses. Tuberculosis, 143, 102414. https://doi.org/10.1016/j.tube.2023.102414
Meserve, K., - (2025). Multiplexed cytokine profiling identifies diagnostic signatures for latent tuberculosis and reactivation risk stratification. PLOS ONE, 20, e0326896. https://doi.org/10.1371/journal.pone.0316648
Mishra, R., - (2023). Mechanopathology of biofilm-like Mycobacterium tuberculosis cords. Cell, 186(22), 4862–4878.e24. https://doi.org/10.1016/j.cell.2023.09.021
Mulholland, C. V., Wiggins, T. J., Cui, J., Vilchèze, C., Rajagopalan, S., Shultis, M. W., Reyes-Fernández, E. Z., Jacobs, W. R., Jr., & Berney, M. (2024). Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis. Nature Microbiology, 9(6), 1607–1618. https://doi.org/10.1038/s41564-024-01697-8
Palanivel, J., Sounderrajan, V., Thangam, T., Rao, S. S., Harshavardhan, S., & Parthasarathy, K. (2023). Latent tuberculosis: Challenges in diagnosis and treatment, perspectives, and the crucial role of biomarkers. Current Microbiology, 80(12), 392. https://doi.org/10.1007/s00284-023-03491-x
Pisu, D., Johnston, L., Mattila, J. T., & Russell, D. G. (2024). The frequency of CD38⁺ alveolar macrophages correlates with early control of Mycobacterium tuberculosis in the murine lung. Nature Communications, 15(1), 8522. https://doi.org/10.1038/s41467-024-52846-w
Queiroz, A., & Riley, L. W. (2017). Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response. Revista da Sociedade Brasileira de Medicina Tropical, 50, 9–18. https://doi.org/10.1590/0037-8682-0230-2016
Queval, C. J., Brosch, R., & Simeone, R. (2017). The macrophage: A disputed fortress in the battle against Mycobacterium tuberculosis. Frontiers in Microbiology, 8, 2284. https://doi.org/10.3389/fmicb.2017.02284
Queval, C. J., Song, O.-R., Carralot, J.-P., Saliou, J.-M., Bongiovanni, A., Deloison, G., Deboosere, N., Jouny, S., Iantomasi, R., Delorme, V., Debrie, A.-S., Park, S.-J., Costa Gouveia, J., Tomavo, S., Brosch, R., Yoshimura, A., Yeramian, E., & Brodin, P. (2017). Mycobacterium tuberculosis controls phagosomal acidification by targeting CISH-mediated signaling. Cell Reports, 20(13), 3188–3198. https://doi.org/10.1016/j.celrep.2017.08.080
Radhakrishnan, S. K., & Sundaramurthy, V. (2026). The lipid language of tuberculosis: Mycobacterium tuberculosis surface molecules in host interaction and drug resistance. mBio. https://doi.org/10.1128/mbio.03959-25
Rai, R., Singh, V., Mathew, B. J., Singh, A. K., & Chaurasiya, S. K. (2022). Mycobacterial response to an acidic environment: Protective mechanisms. Pathogens and Disease, 80(1), ftac032. https://doi.org/10.1093/femspd/ftac032
Rao, M., Ippolito, G., Mfinanga, S., Ntoumi, F., Yeboah-Manu, D., Vilaplana, C., Zumla, A., & Maeurer, M. (2019). Latent TB infection (LTBI): Mycobacterium tuberculosis pathogenesis and the dynamics of the granuloma battleground. International Journal of Infectious Diseases, 80(Suppl. 1), S58–S61. https://doi.org/10.1016/j.ijid.2019.01.022
Rens, C., Chao, J. D., Sexton, D. L., Tocheva, E. I., & Av-Gay, Y. (2021). Roles for phthiocerol dimycocerosate lipids in Mycobacterium tuberculosis pathogenesis. Microbiology, 167(3), 001042. https://doi.org/10.1099/mic.0.001042
Rothchild, A. C., Olson, G. S., Nemeth, J., Amon, L. M., Mai, D., Gold, E. S., Diercks, A. H., & Aderem, A. (2019). Alveolar macrophages generate a noncanonical NRF2-driven transcriptional response to Mycobacterium tuberculosis in vivo. Science Immunology, 4(37), eaaw6693. https://doi.org/10.1126/sciimmunol.aaw6693
Salina, E. G., & Makarov, V. (2022). Mycobacterium tuberculosis dormancy: How to fight a hidden danger. Microorganisms, 10(12), 2334. https://doi.org/10.3390/microorganisms10122334
Samuels, A. N., Wang, E. R., Harrison, G. A., Valenta, J. C., & Stallings, C. L. (2022). Understanding the contribution of metabolism to Mycobacterium tuberculosis drug tolerance. Frontiers in Cellular and Infection Microbiology, 12, 958555. https://doi.org/10.3389/fcimb.2022.958555
Sankar, P., & Mishra, B. B. (2023). Early innate cell interactions with Mycobacterium tuberculosis in protection and pathology of tuberculosis. Frontiers in Immunology, 14, 1260859. https://doi.org/10.3389/fimmu.2023.1260859
Sawyer, A. J., Patrick, E., Edwards, J., Wilmott, J. S., Fielder, T., Yang, Q., Barber, D. L., Ernst, J. D., Britton, W. J., Palendira, U., Chen, X., & Feng, C. G. (2023). Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis. Journal of Experimental Medicine, 220(6), e20221392. https://doi.org/10.1084/jem.20221392
Shah, M., & Dorman, S. E. (2021). Latent tuberculosis infection. New England Journal of Medicine, 385(24), 2271–2280. https://doi.org/10.1056/NEJMcp2108501
Shahzad, F., Bashir, N., Ali, A., Nadeem, A., Ammar, A., Kashif, M., Javaid, K., Jahan, S., Tahir, R., Rizwan, M., Mushtaq, A., & Afzal, N. (2022). SLC11A1 genetic variation and low expression may cause immune response impairment in TB patients. Genes & Immunity, 23(2), 85–92. https://doi.org/10.1038/s41435-022-00165-9
Son, S.-H., Lee, J., Cho, S.-N., Choi, J.-A., Kim, J., Nguyen, T. D., Lee, S.-A., Son, D., & Song, C.-H. (2023). Herp regulates intracellular survival of Mycobacterium tuberculosis H37Ra in macrophages by regulating reactive oxygen species-mediated autophagy. mBio, 14(5), e01535-23. https://doi.org/10.1128/mbio.01535-23
Srivastava, S., Battu, M. B., Khan, M. Z., Nandicoori, V. K., & Mukhopadhyay, S. (2019). Mycobacterium tuberculosis PPE2 protein interacts with p67phox and inhibits reactive oxygen species production. The Journal of Immunology, 203(5), 1218–1229. https://doi.org/10.4049/jimmunol.1900396
Stokas, H., Rhodes, H. L., & Purdy, G. E. (2020). Modulation of the Mycobacterium tuberculosis cell envelope between replicating and non-replicating persistent bacteria. Tuberculosis, 125, 102007. https://doi.org/10.1016/j.tube.2020.102007
Tiwari, S., Casey, R., Goulding, C. W., Hingley-Wilson, S. M., & Jacobs, W. R., Jr. (2019). Infect and inject: How Mycobacterium tuberculosis exploits its major virulence-associated Type VII secretion system, ESX-1. Microbiology Spectrum, 7(3), BAI-0024-2019. https://doi.org/10.1128/MicrobiolSpec.BAI-0024-2019
Varshney, D., - (2022). Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection. Cytokine, 152, 155821. https://doi.org/10.1016/j.cyto.2022.155821
Veatch, A. V., & Kaushal, D. (2018). Opening Pandora's box: Mechanisms of Mycobacterium tuberculosis resuscitation. Trends in Microbiology, 26(2), 145–157. https://doi.org/10.1016/j.tim.2017.08.001
Vilchèze, C., & Jacobs, W. R., Jr. (2019). The isoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis. Journal of Molecular Biology, 431(18), 3450–3461. https://doi.org/10.1016/j.jmb.2019.02.016
Yadav, U., Kumar, P., & Rai, V. (2021). FokI polymorphism of the vitamin D receptor (VDR) gene and susceptibility to tuberculosis: Evidence through a meta-analysis. Infection, Genetics and Evolution, 92, 104871. https://doi.org/10.1016/j.meegid.2021.104871
Zihad, S. M. N. K., Sifat, N., Islam, M. A., Al-Hossain, A. S. M. M., Sikdar, K. Y. K., Sarker, M. M. R., Shilpi, J. A., & Uddin, S. J. (2023). Role of pattern recognition receptors in sensing Mycobacterium tuberculosis. Heliyon, 9(10), e20535. https://doi.org/10.1016/j.heliyon.2023.e20535
