Mycobacterium tuberculosis
"Tuberculosis
is as old as humanity itself — only by working together can we turn the tide
against this ancient killer (Global
Tuberculosis Report 2024, 2024)."
Introducing a Microbial Mastermind
Mycobacterium
tuberculosis is a sneaky and resilient bacterium that
causes tuberculosis (TB): a deadly disease that has taken millions of lives for
decades (Kyu
et al., 2018). This invader mainly affects the
lungs but can also spread to other organs causing havoc (Baykan
et al., 2022).
What
makes it almost invincible? Their cell walls: made up of a complex mixture of
components makes them resist many antibiotics and survive harsh circumstances (Batt
et al., 2020). TB can get to a person by just a
sneeze or a cough from an infected person as it spreads through air (Patterson
& Wood, 2019). However, we still have a chance to
defeat this invisible enemy by early diagnosis, effective treatment and
preventive measures.
A Deadly Intruder on the Move
Tuberculosis
is an airborne disease and can get transmitted easily (Dinkele
et al., 2022). When a person infected with TB
coughs, sneezes or even speaks, hundreds of tiny droplets containing Mycobacterium
tuberculosis can get released in to the air and remain suspended for
hours; mostly in crowded and poorly ventilated spaces (Patterson
& Wood, 2019). And if someone inhale these
droplets, these invisible enemies can enter to their lungs and cause infection.
Therefore, it’s important to have proper ventilation and the use of masks can be
helpful (Lee,
2016).
M. tuberculosis v Immune System
With the entry of this tiny pathogen, a microscopic battle is about to unfold inside the lungs. These invaders are taken up by alveolar macrophages: immune cells that works as the first line of defence in lungs (Hauwermeiren & Lamkanfi, 2023). Nevertheless, these pathogens hide inside the phagosome of these cells and inhibit the phagosome-lysosome fusion with the help of virulence factors. This leads to the survival and multiplication of bacteria (Queval et al., 2017).
After
a few weeks, infected macrophages start to alert the immune system (Flynn
et al., 2011). As response, immune cells like
macrophages, dendritic cells, neutrophils and T-cells starts building a
fortress called granuloma that can trap the bacteria and contain the infection (Ramakrishnan,
2012).
Figure 1: Typical Structure of a TB Granuloma. This diagram
illustrates the different types of immune cells that make up a TB granuloma (Pai et al., 2016).
However, Mycobacterium tuberculosis knows exactly how to outsmart these immune strategies. They release chemical signals to attract weak immune cells that would make a barrier against killer T-cells from reaching them (Chandra et al., 2022). Inside this fortress, these invaders stay hidden and asleep for years. This is called latent TB. But if the immune system weakens due to factors like stress or illness, they strike back causing active TB disease (Zhai et al., 2019).
The immune system uses several steps to fight this smart and dangerous enemy.
- CD4⁺ T cells release interferon gamma (IFN-γ) as signals to activate macrophages to kill the pathogen.
- CD8⁺ T Cells kill infected cells.
- Cytokines and chemokines coordinate the
attack.
- B-cells and antibodies help locate the pathogens (Liu et al., 2017).
Despite
all these mechanisms, Mycobacterium tuberculosis is not ready to give up
the fight. They inhibit dendritic cell activity, that prevents antigen
presentation and thereby postpones T-cell activation (Mihret,
2012).
They can also change the behaviour of macrophages from pro-inflammatory to
anti-inflammatory and weaken the immunity (Refai
et al., 2018). And if the fortress collapse, it
will lead to lung damage and cavitation as its’ caseous core can flow into
airways and destroy healthy tissue (Kayongo
et al., 2023).
Detection Systems: How To Screen and Diagnose Tuberculosis
Ever wonder how to detect these invaders before someone gets sick? Screening tests like Mantoux tuberculin skin test (TST) can detect TB before they start showing symptoms. But it can give false positives to the individuals vaccinated with BCG (Muñoz et al., 2015). Interferon‑Gamma Release Assay (IGRA), that measures immune cells' response to TB antigens can give you more accurate results than TST (Lu et al., 2016). If the symptoms start showing, we can use chest x-rays and computer-assisted detection systems (CAD) for TB identification (Melendez et al., 2016).
If TB is suspected, the doctors can do confirmation tests like following.
- Sputum smear microscopy (Ziehl–Neelsen) -
a rapid, low-cost and a moderately sensitive test used often in clinical
laboratories (Umair
et al., 2020).
- Mycobacterial cultures - more specific,
accurate and detect small amounts of bacteria. However, these may take weeks to
show results (Campelo
et al., 2021).
- Xpert MTB/RIF molecular test - provide results within 2 hours and can detect rifampicin resistance with high sensitivity and specificity (Boehme et al., 2011).
Counterattack on Tuberculosis with Treatments
We need treatments to overcome TB. Even though some strains are easily eliminated by drugs, some stay resistant and survives.
Drug‑Susceptible TB
Patients can be treated using a 6-month course of four key antibiotics—isoniazid, rifampicin, pyrazinamide, and ethambutol. And it can be shortened to just 4 months using combinations like rifapentine and moxifloxacin. It is important to take each dose to prevent drug resistance (Pai et al., 2016).
· Drug‑Resistant TB
Figure
2 shows a treatment regimen for multi-drug resistant (MDR-TB) tuberculosis (Seung
et al., 2015).
Figure 2: Design of a MDR-TB regimen (Seung et al., 2015).
Mapping the Enemy
WHO Global Tuberculosis Report 2024 confirms that TB has caused 10.8 million cases and 1.25 million deaths in 2023 which is highly concerning (Global Tuberculosis Report 2024, 2024). There is a significant risk of disease activation because approximately one-third of the world's population carries latent TB, and in places like sub-Saharan Africa and South Asia, up to 50% of people do. The threat is worsened by HIV and malnutrition, and rising drug-resistant TB strains (Semba et al., 2010).
TB
is not only a medical problem; our social structures and surroundings have a
significant impact on it. TB risk is increased by poverty, overcrowding,
humidity, air pollution, and inadequate health services. We need better living
conditions, cleaner air, and more competent public health services that target
disadvantaged people if we are to effectively fight tuberculosis (Liyew
et al., 2024).
Conclusion
Despite its long history, TB is still a deadly and sneaky threat in the modern world. Millions of people are affected to this day even with the improvements in diagnosis and treatment. We can fight TB by understanding how it spreads and survives within the lungs. There’s a chance to end this global threat with the help of ongoing research and public health projects. However, awareness, action and dedication are much needed.
References
Batt,
S. M., Burke,
C. E., Moorey, A. R., & Besra, G. S. (2020). Antibiotics and resistance:
The two-sided coin of the mycobacterial cell wall. The Cell Surface, 6,
100044. https://doi.org/10.1016/j.tcsw.2020.100044
Baykan, A. H., Sayiner, H. S., Aydin, E., Koc, M.,
Inan, I., & Erturk, S. M. (2022). Extrapulmonary tuberculosıs: An old but
resurgent problem. Insights into Imaging, 13(1), 39.
https://doi.org/10.1186/s13244-022-01172-0
Boehme, C. C., Nicol, M. P., Nabeta, P., Michael, J.
S., Gotuzzo, E., Tahirli, R., Gler, M. T., Blakemore, R., Worodria, W., Gray,
C., Huang, L., Caceres, T., Mehdiyev, R., Raymond, L., Whitelaw, A., Sagadevan,
K., Alexander, H., Albert, H., Cobelens, F., … Perkins, M. D. (2011).
Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the
Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: A
multicentre implementation study. The Lancet, 377(9776),
1495–1505. https://doi.org/10.1016/S0140-6736(11)60438-8
Campelo, T. A., Cardoso de Sousa, P. R., Nogueira, L.
de L., Frota, C. C., & Zuquim Antas, P. R. (2021). Revisiting the methods
for detecting Mycobacterium tuberculosis: What has the new millennium brought
thus far? Access Microbiology, 3(8), 000245.
https://doi.org/10.1099/acmi.0.000245
Chandra, P., Grigsby, S. J., & Philips, J. A.
(2022). Immune evasion and provocation by Mycobacterium tuberculosis. Nature
Reviews Microbiology, 20(12), 750–766.
https://doi.org/10.1038/s41579-022-00763-4
Dinkele, R., Gessner, S., McKerry, A., Leonard, B.,
Leukes, J., Seldon, R., Warner, D. F., & Wood, R. (2022). Aerosolization of
Mycobacterium tuberculosis by Tidal Breathing. American Journal of
Respiratory and Critical Care Medicine, 206(2), 206–216.
https://doi.org/10.1164/rccm.202110-2378OC
Flynn, J. L., Chan, J., & Lin, P. L. (2011).
Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal
Immunology, 4(3), 271–278. https://doi.org/10.1038/mi.2011.14
Global Tuberculosis Report 2024 (1st ed).
(2024). World Health Organization.
Hauwermeiren, F. V., & Lamkanfi, M. (2023).
Tuberculosis: The tug of war between pathogen and inflammasome. Current
Biology, 33(1), R33–R36. https://doi.org/10.1016/j.cub.2022.11.025
Kayongo, A., Nyiro, B., Siddharthan, T., Kirenga, B.,
Checkley, W., Lutaakome Joloba, M., Ellner, J., & Salgame, P. (2023).
Mechanisms of lung damage in tuberculosis: Implications for chronic obstructive
pulmonary disease. Frontiers in Cellular and Infection Microbiology, 13.
https://doi.org/10.3389/fcimb.2023.1146571
Kyu, H. H., Maddison, E. R., Henry, N. J., Ledesma, J.
R., Wiens, K. E., Reiner, R., Biehl, M. H., Shields, C., Osgood-Zimmerman, A.,
Ross, J. M., Carter, A., Frank, T. D., Wang, H., Srinivasan, V., Agarwal, S.
K., Alahdab, F., Alene, K. A., Ali, B. A., Alvis-Guzman, N., … Murray, C. J. L.
(2018). Global, regional, and national burden of tuberculosis, 1990–2016:
Results from the Global Burden of Diseases, Injuries, and Risk Factors 2016
Study. The Lancet Infectious Diseases, 18(12), 1329–1349.
https://doi.org/10.1016/S1473-3099(18)30625-X
Lee, S. H. (2016). Tuberculosis Infection and Latent
Tuberculosis. Tuberculosis and Respiratory Diseases, 79(4),
201–206. https://doi.org/10.4046/trd.2016.79.4.201
Liu, C. H., Liu, H., & Ge, B. (2017). Innate
immunity in tuberculosis: Host defense vs pathogen evasion. Cellular and
Molecular Immunology, 14(12), 963–975.
https://doi.org/10.1038/cmi.2017.88
Liyew, A. M., Clements, A. C. A., Akalu, T. Y.,
Gilmour, B., & Alene, K. A. (2024). Ecological-level factors associated
with tuberculosis incidence and mortality: A systematic review and
meta-analysis. PLOS Global Public Health, 4(10), e0003425.
https://doi.org/10.1371/journal.pgph.0003425
Lu, P., Chen, X., Zhu, L., & Yang, H. (2016).
Interferon-Gamma Release Assays for the Diagnosis of Tuberculosis: A Systematic
Review and Meta-analysis. Lung, 194(3), 447–458.
https://doi.org/10.1007/s00408-016-9872-5
Melendez, J., Sánchez, C. I., Philipsen, R. H. H. M.,
Maduskar, P., Dawson, R., Theron, G., Dheda, K., & van Ginneken, B. (2016).
An automated tuberculosis screening strategy combining X-ray-based
computer-aided detection and clinical information. Scientific Reports, 6(1),
25265. https://doi.org/10.1038/srep25265
Mihret, A. (2012). The role of dendritic cells in
Mycobacterium tuberculosis infection. Virulence, 3(7), 654–659.
https://doi.org/10.4161/viru.22586
Muñoz, L., Stagg, H. R., & Abubakar, I. (2015).
Diagnosis and Management of Latent Tuberculosis Infection. Cold Spring
Harbor Perspectives in Medicine, 5(11), a017830.
https://doi.org/10.1101/cshperspect.a017830
Pai, M., Behr, M. A., Dowdy, D., Dheda, K., Divangahi,
M., Boehme, C. C., Ginsberg, A., Swaminathan, S., Spigelman, M., Getahun, H.,
Menzies, D., & Raviglione, M. (2016). Tuberculosis. Nature Reviews
Disease Primers, 2(1), 16076. https://doi.org/10.1038/nrdp.2016.76
Patterson, B., & Wood, R. (2019). Is cough really
necessary for TB transmission? Tuberculosis, 117, 31–35.
https://doi.org/10.1016/j.tube.2019.05.003
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
Ramakrishnan, L. (2012). Revisiting the role of the
granuloma in tuberculosis. Nature Reviews Immunology, 12(5),
352–366. https://doi.org/10.1038/nri3211
Refai, A., Gritli, S., Barbouche, M.-R., & Essafi,
M. (2018). Mycobacterium tuberculosis Virulent Factor ESAT-6 Drives Macrophage
Differentiation Toward the Pro-inflammatory M1 Phenotype and Subsequently
Switches It to the Anti-inflammatory M2 Phenotype. Frontiers in Cellular and
Infection Microbiology, 8. https://doi.org/10.3389/fcimb.2018.00327
Semba, R. D., Darnton-Hill, I., & de Pee, S.
(2010). Addressing tuberculosis in the context of malnutrition and HIV
coinfection. Food and Nutrition Bulletin, 31(4 Suppl), S345-364.
Seung, K. J., Keshavjee, S., & Rich, M. L. (2015).
Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. Cold
Spring Harbor Perspectives in Medicine, 5(9), a017863.
https://doi.org/10.1101/cshperspect.a017863
Umair, M., Siddiqui, S. A., & Farooq, M. A.
(2020). Diagnostic Accuracy of Sputum Microscopy in Comparison With GeneXpert
in Pulmonary Tuberculosis. Cureus. https://doi.org/10.7759/cureus.11383
Zhai, W., Wu, F., Zhang, Y., Fu, Y., & Liu, Z.
(2019). The Immune Escape Mechanisms of Mycobacterium Tuberculosis. International
Journal of Molecular Sciences, 20(2), Article 2.
https://doi.org/10.3390/ijms20020340
