by Casey Leung and Veronika Saykova
Introduction
Mycobacterium tuberculosis is a pathogenic bacterium that causes tuberculosis, commonly known as TB. The bacteria were first identified in 1882 by German microbiologist Robert Koch. The emergence of M. tuberculosis as a human pathogen is not well understood, but tuberculosis became epidemic among humans in the seventeenth century, causing the Great White Plague in Europe. Humans are the only known reservoirs of M. tuberculosis.
Disease
Tuberculosis is an infectious disease caused by Mycobacterium Tuberculosis. The bacteria primarily infect the lungs, known as pulmonary tuberculosis (see Figure 1); but it can also spread to other parts of the body, known as extrapulmonary tuberculosis. Transmission from one person to another occurs when a person with pulmonary tuberculosis speaks, coughs or sneezes. The bacteria are expelled in micro droplets, which are suspended in air and then breathed in by a susceptible person. When inhaled, there are three distinct outcomes: 1) the inhaled bacteria are completely eradicated by the immune system so do not establish an infection, 2) the bacteria remain alive but inactive in the body, and 3) the active bacteria cause tuberculosis disease.
Figure 1: Chest x-ray of a person with pulmonary tuberculosis. Areas of the lungs (black) that are infected by M. tuberculosis appear as white haze (circled in red). Source: Public Health Image Library, Centers for Disease Control and Prevention (1972).
The inactive state is called latent tuberculosis infection and is the most common. In this state, the infected person is not sick and do not develop tuberculosis disease. Latent infection causes no symptoms and is not contagious. However, approximately 10% of people with latent infection eventually progress into active, which can occur immediately after infection up to decades later.
In the active state, the bacteria multiply in the body and cause contagious tuberculosis disease. Symptoms include persistent coughing, coughing up blood or mucus, chest pain, fatigue, weight loss, loss of appetite, fever and night sweats. If left untreated, it causes tissue damage in the lungs, resulting in respiratory failure and can spread to other parts of the body.
Epidemiology
Overall, mortality due to tuberculosis has declined by 47% since 1990. But it is estimated that about one-third of the world’s population has latent tuberculosis. Although only a minority of those infected develop active tuberculosis, it is still a major health problem each year and ranks alongside HIV as a leading infectious cause of death worldwide. Drug-resistant tuberculosis is also being an increasing concern. According to the latest World Health Organization annual report on tuberculosis, there was an estimate of 9.6 million cases and 1.5 million deaths in 2014 worldwide. However, the numbers vary significantly among different countries. In 2014, about 90% occurred in Africa and Asia while only 3% occurred in the Americas. The largest number of cases occurred in India, Indonesia, China, Nigeria, Pakistan and South Africa.
Figure 2: Estimated prevalence of tuberculosis per 100,000 people per country in 2007. Developing countries in Africa and Asia have the highest incident rates (shown in yellow), while countries in North America, parts of Europe, Australia and New Zealand have the lowest incident rates (shown in blue). Source: Wikimedia Commons, Eubulides (2009).
People in low-income developing countries are more likely to develop tuberculosis largely due to high rates of HIV infection and are less likely to be diagnosed or receive treatments. People with HIV are more susceptible to tuberculosis, with 12% of the 2014 cases being HIV-positive. In particular, Africa alone accounted for 74% of the total number of HIV-positive cases. Without proper treatment, the infected individuals are more likely to spread the disease to the larger community.
Virulence factors
In the latent state, M. tuberculosis remains alive but inactive due to the formation of granulomas, where the bacteria are surrounded by infected cells of the immune system. The bacteria are hidden and continue surviving in the centre then become active when the immune system is compromised and develop into tuberculosis disease.
By comparing the genetic sequences of the virulent Mycobacterium Tuberculosis and of the closely-related but non-virulent Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine strain, a region of 9 genes called RD1 is discovered to contribute to the virulence of the bacteria. This region is responsible for the production of a protein called ESAT-6 that is secreted outside of the bacteria to recruit more immune cells to form the granulomas. If there is a disruption in the RD1 genes, the protein is either not produced or not secreted then the bacteria are no longer virulent. The bacteria will be unable to trigger the formation of granulomas or grow in lungs.
Treatments
Preliminary diagnostic for tuberculosis is commonly done using tuberculin skin test or blood test. If either tested positive, it identifies that the person has been exposured to tuberculosis bacteria, but further tests such as chest x-ray are needed to verify the state of infection: latent or active.
Current treatments for latent tuberculosis include a regimen of isoniazid over a 9-month period or a combination of isoniazid and rifapentine for 3 months. Standard treatment for active tuberculosis has a success rate of approximately 85%. It requires a 6-month long regimen of multiple first-line drugs: isoniazid, rifampicin, ethambutol and pyrazinamide for the first 2 months followed by an addition 4 months of isoniazid and rifampicin. In cases where the bacteria are resistant to the first-line drugs, second-line drugs are used for a much longer regimen of 20 months.
BCG vaccination can prevent tuberculosis disease in children and is widely used after birth in countries with high prevalence of tuberculosis. It is not widely used in countries such as Canada and the United States where tuberculosis is uncommon. The vaccine decreases the risk of getting an infection in children by about 20% and decreases the risk of an infection turning into disease by nearly 60%. However, the vaccine fails to protect against tuberculosis in adults, and an effective vaccine in adults still remains elusive to date. Currently, a number of new drugs and vaccines against tuberculosis are in development and are being tested in different stages of clinical trials.
References
Center for Disease Control and Prevention. (2012). CDC | Tuberculosis (TB) | Basic TB Facts. Retrieved 20 November 2015, from http://www.cdc.gov/tb/topic/basics/default.htm
Behr, M. A., & Sherman, D. R. (2007). Mycobacterial virulence and specialized secretion: same story, different ending. Nat Med, 13(3), 286-287. Retrieved from http://dx.doi.org/10.1038/nm0307-286
Phuah, J. Y., Mattila, J. T., Lin, P. L., & Flynn, J. L. (2012). Activated B Cells in the Granulomas of Nonhuman Primates Infected with Mycobacterium tuberculosis. The American Journal of Pathology, 181(2), 508-514. doi:http://dx.doi.org/10.1016/j.ajpath.2012.05.009
Talbot, E. A., & Raffa, B. J. (2015). Chapter 92 – Mycobacterium tuberculosis. In Y.-W. T. S. L. P. Schwartzman (Ed.), Molecular Medical Microbiology (Second Edition) (pp. 1637-1653). Boston: Academic Press.
World Health Organization. (2015). Global Tuberculosis Report 2015. Geneva. Retrieved from http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1
Mechanisms of Pathogenicity 