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Tuberculosis (TB) is an infectious disease that is caused by a gram positive (does not stain from crystal violet wash) bacillus Mycobacterium tuberculosis and it has a rod shape1. It is aerobic(requires O2) and that is why it is most often found in the most aerated parts of the lungs. It reproduces inside the host cell that means it's facultative intracellular parasite1. It is the second most deadly infectious disease after HIV. It is known to mainly affect the lungs of the individual- pulmonary TB. It can affect other organs of the body as well- extra pulmonary TB. It is a contagious disease and spreads only through air and not because of direct physical contact with the affected person. The bacteria from the person affected with pulmonary TB get dispersed in the air in form of droplets when they sneeze, cough, talk and so on which is then inhaled by healthy individuals around them2.
Having Mycobacterium tuberculosis (M. tuberculosis)doesn't necessarily mean that the person has TB disease. There are two forms of TB one is the latent form where an individual has the bacteria but doesn't show any signs and symptoms and is not contagious. The other form is the active form of TB where the individual shows signs and symptoms and is contagious. The most common symptoms in individual infected with active TB are coughing sputum or blood, chest pains, weakness, weight loss, fever and night sweats3.
However studies show that about 5- 10% of the people with latent TB will develop active TB with in the first two years of getting infected with M. tuberculosis3.TB is known to affect young males more than females2 and especially people in low and middle income countries where there is malnutrition, poor sanitation which results in poor innate immunity making people more susceptible to getting infected with M. tuberculosis and then developing active TB2,4.
TB is curable if diagnosed and treated in time with first line of drugs for 6 months3. If these first line of drugs are not administered for 6 months as directed by the physician then they can lead to drug resistant bacteria. Bacteria can be resistant to first line of drug leading to multidrug resistant (MDR) bacteria. To treat MDR bacteria, physician will have to give second line of drugs and if these bacteria become resistant to these drugs as well, that will leading to extensively drug resistant (XDR) bacteria, that is very hard to treat5. Also, there are many strategies like DOTS strategy and Stop TB Strategy that can help prevent TB from developing in first place and save millions of lives2. There has been a lot of research being done using animal models such as guinea pigs and mouse that could help scientist better understand the pathology, virulence and cure of TB6,7.
Transmission(induces latent TB)
Tuberculosis is an airborne infection and humans are the only reservoirs of TB infection and the disease. It is spread in form of droplet through the air transmission. Tiny droplets of diameter 1-5 microns contain M. tuberculosis bacteria in them that can spread up to 1 meter in distance from the source3. These droplets are released when an individual infected with pulmonary TB sneezes, coughs, shouts, sings etc. These droplets cannot be spread because of shaking hands, sharing food, kissing or any other task requiring physical contact with the infected person1,2,3. The droplets stay suspended in the air for several hours and are transmitted to other people when they inhale these droplets. The droplets travel down person's respiratory tract and infects them as it reaches their lungs. A person needs to inhale about 10 of the M. tuberculosis infected droplets to get the infection. Person infected with the appropriate amount of droplets gets latent TB where they only have the bacteria and not the disease1. If there immune system is healthy at the time of contact with the infection, it will fight off the bacteria and stop it from growing and developing active TB. But if the person coming in contact with infected air is immunosuppressant i.e. their immune system is unable to fight the bacteria, leading to rapid multiplication of the bacteria that turns latent TB to active TB2,3.
An individual could be immunosuppressant because of many reasons such as HIV, diabetes, alcohol abuse, poor nutrition, terminal cancer, Vitamin D deficiency. These factors increase the virulence of the bacteria and such individuals are likely to develop TB disease within couple of weeks from the time of infection6. However it is possible that people who were healthy at the time of contact with the infection did not develop the disease soon after getting infected. But if they are left untreated for the TB infection, there is a high chance that they will develop it within the 2 years from infection or whenever they become immunosuppressant2,3. Chances of both immunosuppressant and non immunosuppressant individuals developing the disease are increased with prolonged exposure to people in poorly ventilated, TB prone regions3.
Healthy people who do not develop TB after getting infected do not have the disease or any symptoms of it. Therefore they cannot spread the disease to others in any way. However immunosuppressant individuals who developed the disease either right after getting infected or later in life can spread the bacteria to others through air1,2,3.
Tuberculosis, despite being a curable disease is a global threat and even though there has been a 45% decline in TB mortality since 1990 and it is continuously declining, it still has a very high prevalence worldwide especially in the African regions. There were 8.6 million new cases of TB reported in 2012 and 1.3 millions of those people died because of TB disease, especially the people who also had HIV. Interventions have been going on around the world since WHO first declared TB as a global threat in 1993. Since 1993, efforts to control TB through programs like DOTs and vaccination camps they have saved 22 million lives2 but in countries like India these vaccinations haven't been as successful and have only prevented 5% of the total cases happening in India6. These programs have been the most successful in high income countries that have good health care to prevent TB such as Europe, Canada, USA, Japan, Australia2. But low income countries where people do not have access to health care system accounted for 95% of the TB cases and deaths2,3. Among those low income countries the highest TB cases in 2012 were reported in South- East Asia and Western Pacific Regions that accounted for 58% of the world TB cases. African region accounted for a quarter of the world TB cases, in India and China 26% and 12% respectively. Africa and Swaziland had the highest incidence of TB per capita. In both income rich and income poor countries the TB rates are predicated to go down; faster decline is high income and slower decline in the latter. However it is estimated that the HIV- positive related TB cases are going to rise around the world in general due to the global rise in HIV infection2.
Pathogenesis and Immune response
Robert Koch was the first one to define the causes of TB using a guinea pig model. Koch isolated the M. tuberculosis bacteria from an infected person and inoculated the guinea pig with the pure culture of the bacteria. He observed that this produced similar lesions that were seen on the infected humans6,7. Since then many other animal models have been used to inoculate pure cultures of M. tuberculosis bacterium in them in order to study the pathogenesis of TB, it's prevention and cure. These animal models include rabbits, guinea pigs, mice etc6,7. The reason for use of different animal models is that each of these models show different pathogenesis for TB and are related to human hosts in one way or another. Hence, providing wider range of information6.
The reason guinea pigs and rabbits were being used widely to study TB was because of their high susceptibility to TB disease and high relatedness to human hosts. For rabbits the pathology of TB also has 5 stages just like in humans, making it a good model to understand the different stages leading to the disease6. However guinea pigs have been the most commonly used animal models for infectious disease out of all because of their higher relatedness to humans in terms of infectious diseases, in general. In regards to TB, guinea pigs respond well to anti- tuberculosis antibiotics, making them perfect model for testing the efficiency of different antimycobacterial drugs and vaccines. Also they are predicted to be quite useful for research on multidrug resistant TB6,7.
Mouse model has also been used quite a lot because of its efficient innate immunity that makes it highly resistant to the disease. Also, mouse models are cost effective which is a great advantage for testing different drugs and vaccines for TB6,7. Information gathered from testing of vaccines and drugs on mouse models has provided insight into how acquired immunity can effectively prevent TB6.
Despite the differences in the pathologies and uses each animal model possess, all the animal models have been known to become highly venerable to TB disease due to malnutrition. That is because malnutrition plays a huge factor in cell- mediated immune response (disrupt T-cell functioning) and if the host lacks innate immunity, they are less capable of defending the body from tuberculosis disease6.
Treatment/ Vaccine/ Policy issues(global plans to stop TB)
The first step of treating someone is diagnosing what type of TB they have. Based on the type of TB i.e. latent TB, active TB or drug resistant TB, the treatment and prevention strategies will be different.
Pulmonary TB is the common form of TB and some of the first indicators of TB would be a cough that lasts more than 3 weeks,coughing up blood - hemoptysis or if the person experiences chest pain. If any of these symptoms exist, the next step would be to do a thorough medical checkup of the person suspected to have TB. During the medical check up the physician would gather the information about the individuals history of exposure to TB prone areas because that can greatly increase the chances of getting the infection. Also the physician would check for any medical history of the patient that may significantly increase the chances of latent TB becoming active such as HIV and cancer.
1Todar, Todar's Online Textbook of Bacteriology, textbookofbacteriology.net/tuberculosis.html (accessed 03/15/14)
2 World Health Organization . Global Tuberculosis Report 2013. WHO Press: Geneva, Switzerland; 2013.
3 CDC, Core Curriculum on Tuberculosis: What the Clinician Should Know, 2013, http://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf (accessed 03/16/14)
4 Arora, P, Foster, E.L, Porcelli, S.A. CD1d and Natural Killer T Cells in Immunity to Mycobacterium tuberculosis. 2013. 199-223
5 Shim, T.S, Wook Jo. K. Medical Treatment of Pulmonary Multidrug Resistant Tuberculosis. 45(4):367-374
6 Gupta, U.D, Katoch, V.M. Animals Models of Tuberculosis. 2005. Elsevier. 85:277-293
7 Young, D. Infectious disease: Tuberculosis. 2009. Eur. J. Immunol. 39: 2011-2014
8Delogu, G, Sali, M, Fadda, G. The Biology of Mycobacterium Tuberculosis Infection. 2013. Mediterr J Hematol Infect Dis. 5(1)