Microbial Bioactives
Microbial Bioactives | Online ISSN 2209-2161
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Volume 6 Number 1 2023
REVIEWS (Open Access)
Understanding the Complexity of Latent Tuberculosis: Biology, Diagnosis, and Treatment Challenges
Most Farhana Akter 1, Md. Robiul Islam 1, Syed Atiq Hussain 1, Anwar Hossain 1, Md Sohel Rana 1*
Microbial Bioactives 6 (1) 1-16 https://doi.org/10.25163/microbbioacts.6110675
Submitted: 20 May 2023 Revised: 13 July 2023 Accepted: 21 July 2023 Published: 23 July 2023
Abstract
Latent tuberculosis infection (LTBI) represents one of the most enduring challenges in global infectious disease control, affecting nearly one-quarter of the world’s population and serving as a vast reservoir for future active tuberculosis (TB) cases. Unlike active TB, latency is characterized by the long-term persistence of Mycobacterium tuberculosis (Mtb) in a clinically asymptomatic host, maintained through a delicate balance between bacterial survival strategies and host immune containment. This systematic review explores the biological, microbiological, and host-related determinants that define Mtb dormancy, with particular emphasis on metabolic downregulation, non-replicative persistence, drug tolerance, and the capacity for resuscitation. Evidence from in vitro dormancy models, animal studies, and epidemiological analyses collectively demonstrates that latent infection is not a uniform state but rather a spectrum of physiological phenotypes that differ in culturability, antibiotic susceptibility, and reactivation potential. Dormant bacilli exhibit profound tolerance to first-line antimicrobials, largely due to reduced metabolic activity and altered cellular targets, complicating both treatment and eradication efforts. Host factors—including immune competence, HIV co-infection, metabolic disease, and immunosuppressive therapies—play a decisive role in determining whether latency is maintained or progresses to active disease. Current diagnostic tools, which rely primarily on immune memory, fail to capture bacterial viability or dormancy depth, limiting their prognostic value. By integrating microbial physiology with host risk stratification, this review highlights critical gaps in diagnostics, therapeutics, and modeling approaches, and underscores the need for strategies that specifically target dormant Mtb populations to achieve durable TB control and eventual elimination.
Keywords: Latent tuberculosis; Mycobacterium tuberculosis; dormancy; non-replicating persistence; Drug tolerance; Reactivation risk; Host immunity
References
Batyrshina, Y. R., & Schwartz, Y. S. (2019). Modeling of Mycobacterium tuberculosis dormancy in bacterial cultures. Tuberculosis, 117, 7–17. https://doi.org/10.1016/j.tube.2019.05.005
Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A., & Duncan, K. (2002). Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Molecular Microbiology, 43(3), 717–731. https://doi.org/10.1046/j.1365-2958.2002.02779.x
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
Dartois, V. A., & Rubin, E. J. (2022). Anti-tuberculosis treatment strategies and drug development: Challenges and priorities. Nature Reviews Microbiology, 20, 685–701. https://doi.org/10.1038/s41579-022-00731-y
Deb, C., Lee, C. M., Dubey, V. S., Daniel, J., Abomoelak, B., Sirakova, T. D., Pawar, S., Rogers, L., & Kolattukudy, P. E. (2009). A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS ONE, 4(6), e6077. https://doi.org/10.1371/journal.pone.0006077
Dhillon, J., Lowrie, D. B., & Mitchison, D. A. (2004). Mycobacterium tuberculosis from chronic murine infections that grows in liquid but not on solid medium. BMC Infectious Diseases, 4, 51. https://doi.org/10.1186/1471-2334-4-51
Gangadharam, P. R. (1995). Mycobacterial dormancy. Tubercle and Lung Disease, 76(6), 477–479. https://doi.org/10.1016/0962-8479(95)90521-9
Ha, Y. H., Schneider, P., & Cole, S. T. (2010). Simple model for testing drugs against nonreplicating Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 54(10), 4150–4158. https://doi.org/10.1128/AAC.00474-10
Herrera, V., Perry, S., Parsonnet, J., & Banaei, N. (2011). Clinical application and limitations of interferon-gamma release assays for the diagnosis of latent tuberculosis infection. Clinical Infectious Diseases, 52(8), 1031–1037. https://doi.org/10.1093/cid/cir068
Koul, A., Arnoult, E., Lounis, N., Guillemont, J., & Andries, K. (2011). The challenge of new drug discovery for tuberculosis. Nature, 469, 483–490. https://doi.org/10.1038/nature09657
Koul, A., Dendouga, N., Vergauwen, K., Molenberghs, B., Vranckx, L., Willebrords, R., … & Guillemont, J. (2007). Diarylquinolines target subunit c of mycobacterial ATP synthase. Nature Chemical Biology, 3, 323–324. https://doi.org/10.1038/nchembio884
Makarov, V., Lechartier, B., Zhang, M., Neres, J., van der Sar, A. M., Raadsen, S. A., … & Decosterd, L. A. (2014). Towards a new combination therapy for tuberculosis with next-generation benzothiazinones. EMBO Molecular Medicine, 6(3), 372–383. https://doi.org/10.1002/emmm.201303575
Makarov, V., Manina, G., Mikusova, K., Möllmann, U., Ryabova, O., Saint-Joanis, B., … & Ebright, R. H. (2009). Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 324(5933), 801–804. https://doi.org/10.1126/science.1171583
Manabe, Y. C., Kesavan, A. K., Lopez-Molina, J., Hatem, C. L., Brooks, M., Fujiwara, R., … & Chan, J. (2008). The aerosol rabbit model of TB latency, reactivation, and immune reconstitution inflammatory syndrome. Tuberculosis, 88(3), 187–196. https://doi.org/10.1016/j.tube.2007.11.006
Matsumoto, M., Hashizume, H., Tomishige, T., Kawasaki, M., Tsubouchi, H., Sasaki, H., … & Komatsu, M. (2006). OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Medicine, 3(12), e466. https://doi.org/10.1371/journal.pmed.0030466
McCune, R. M., Feldmann, F. M., Lambert, H. P., & McDermott, W. (1966). Microbial persistence. I. The capacity of tubercle bacilli to survive sterilization in mouse tissues. Journal of Experimental Medicine, 123(3), 445–468. https://doi.org/10.1084/jem.123.3.445
Nuermberger, E., Bishai, W. R., & Grosset, J. H. (2004). Latent tuberculosis infection. Seminars in Respiratory and Critical Care Medicine, 25(4), 317–336. https://doi.org/10.1055/s-2004-829504
O’Garra, A., Redford, P. S., McNab, F. W., Bloom, C. I., Wilkinson, R. J., & Berry, M. P. R. (2013). The immune response in tuberculosis. Annual Review of Immunology, 31, 475–527. https://doi.org/10.1146/annurev-immunol-032712-095939
Oh, C. E., & Menzies, D. (2022). Four months of rifampicin monotherapy for latent tuberculosis infection in children. Clinical and Experimental Pediatrics, 65(5), 214–221. https://doi.org/10.3345/cep.2021.01258
Pai, M., Denkinger, C. M., Kik, S. V., Rangaka, M. X., Zwerling, A., Oxlade, O., & Dowdy, D. W. (2014). Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clinical Microbiology Reviews, 27(3), 3–20. https://doi.org/10.1128/CMR.00034-13
Pawlowski, A., Jansson, M., Sköld, M., Rottenberg, M. E., & Källenius, G. (2012). Tuberculosis and HIV co-infection. PLoS Pathogens, 8(2), e1002464. https://doi.org/10.1371/journal.ppat.1002464
Peña, J. C., & Ho, W. Z. (2015). Monkey models of tuberculosis: Lessons learned. Infection and Immunity, 83(3), 852–862. https://doi.org/10.1128/IAI.02850-14
Peña, J. C., & Ho, W. Z. (2016). Non-human primate models of tuberculosis. Microbiology Spectrum, 4(1). https://doi.org/10.1128/microbiolspec.TBTB2-0007-2016
Peng, T. R., Chen, J. H., Chang, Y. H., Shiang, J. C., Lee, M. C., Lee, C. H., & Wang, J. Y. (2022). Advantages of short-course rifamycin-based regimens for latent tuberculosis infection: An updated network meta-analysis. Journal of Global Antimicrobial Resistance, 29, 378–385. https://doi.org/10.1016/j.jgar.2022.05.006
Sala, C., Dhar, N., Hartkoorn, R. C., Zhang, M., Ha, Y. H., Schneider, P., & Cole, S. T. (2010). Simple model for testing drugs against nonreplicating Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 54(10), 4150–4158.
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
Salina, E., Ryabova, O., Kaprelyants, A., & Makarov, V. (2014). New 2-thiopyridines as potential candidates for killing both actively growing and dormant Mycobacterium tuberculosis cells. Antimicrobial Agents and Chemotherapy, 58(1), 55–60. https://doi.org/10.1128/AAC.01227-13
Scanga, C. A., Mohan, V. P., Joseph, H., Yu, K., Chan, J., & Flynn, J. L. (1999). Reactivation of latent tuberculosis: Variations on the Cornell murine model. Infection and Immunity, 67(9), 4531–4538. https://doi.org/10.1128/IAI.67.9.4531-4538
Scriba, T. J., Coussens, A. K., & Fletcher, H. A. (2016). Human immunology of tuberculosis. Microbiology Spectrum, 4(5), TBTB2-0016-2016. https://doi.org/10.1128/microbiolspec.TBTB2-0016-2016
Shleeva, M. O., Kudykina, Y. K., Vostroknutova, G. N., Suzina, N. E., Mulyukin, A. L., & Kaprelyants, A. S. (2011). Dormant ovoid cells of Mycobacterium tuberculosis are formed in response to gradual external acidification. Tuberculosis, 91(2), 146–154. https://doi.org/10.1016/j.tube.2010.11.003
Sterling, T. R., Villarino, M. E., Borisov, A. S., Shang, N., Gordin, F., Bliven-Sizemore, E., … & Menzies, D. (2011). Three months of rifapentine and isoniazid for latent tuberculosis infection. New England Journal of Medicine, 365(23), 2155–2166. https://doi.org/10.1056/NEJMoa1104875
Takayama, K., Wang, C., & Besra, G. S. (2005). Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clinical Microbiology Reviews, 18(1), 81–101. https://doi.org/10.1128/CMR.18.1.81-101.2005
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
Wayne, L. G., & Hayes, L. G. (1996). An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infection and Immunity, 64(6), 2062–2069. https://doi.org/10.1128/iai.64.6.2062-2069.1996
Zhang, Y., Yew, W. W., & Barer, M. R. (2012). Targeting persisters for tuberculosis control. Antimicrobial Agents and Chemotherapy, 56(5), 2223–2230. https://doi.org/10.1128/AAC.06288-11
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