Tuberculosis

Introduction

Tuberculosis, also known as TB, is an infectious disease that is prevalent in attacking the lungs but also has the capability to invade other parts of the body. It infects the host through particles known as bacilli that are transferred through air. Not only is this microbe highly contagious, but it affects one-third of the worlds population(1). From the one-third infected, the most cases lie in India. Mycobacterium tuberculosis is an etiological agent of tuberculosis in human, which are the only reservoir for this bacterium(2).

Kingdom: Bacteria

Phylum: Actinobacteria

Order: Actinomycetales

Suborder: Corynebacterineae

Family: Mycobacteriaceae

Genus: Mycobacterium

Species: M. tuberculosis

Description of [Tuberculosis]

Description of the microbe

Many cases of tuberculosis are caused by the intracellular pathogen, Mycobacterium tuberculosis. Mycobacteria are non-motile in slender and beaded rod form containing peptidoglycan (4). They exist as obligate aerobics which successfully grow in host tissues of high oxygen and infect mononuclear phagocytes. Mycobacteria require 12 to 18 hours to grow and divide, and more than 3 weeks to develop colonies which is very slow compared to other bacteria (5). All species of mycobacteria are impermeable to Gram stain because their cell wall is hydrophobic and rich in lipid content lacking outer membrane causing cells to clump together which make them immune to Gram + staining. Acid-fast technique is used to stain mycobacteria because their thick waxy cell wall primarily containing mycolic acid which resists ethanol-based and acidic organic solvents decolorization (4). It is an intracellular pathogen that lives in the host and mostly found in water or soil.

Mycobacterium tuberculosis is highly aerobic which exists in the respiratory system of high oxygen levels. Possible ways that Mycobacterium tuberculosis causes infection are through the lungs, invasion of the mucous membranes, and breaking of the skin (3).

Studies have shown that Mycobacterium tuberculosis attains an unusual immunopathology and causes either hypoinflammatory or hyperinflammatory response which reduces its host survival. Hypervirulent Mycobacterium tuberculosis mutants are determined to have deletions in their cell wall modifying regulators which enable them to increase the expression of a granuloma that gives a protective layer which maintains its infection. (3) Mycobacterium tuberculosis’s flexible modular respiratory system enables it to best utilize the energy production in its captive environments. Sulphur metabolism is essential to the virulence and intracellular survival of Mycobacterium tuberculosis. The complex lipid biosynthesis enables Mycobacterium tuberculosis to form thick lipid cell wall which plays a crucial role in its survival and virulence. Dormancy regulon is a process by which Mycobacterium tuberculosis exposes to nitric oxide and carbon monoxide in the absence of aerobic respiration, thus, enabling it to survive in anaerobic environments.

Transmission of disease

Tuberculosis is caused by a rod-shaped bacterium called Mycobacterium tuberculosis (Mtb) which primarily enters the body by inhaling Mtb-contaminated air. Symptoms of Tuberculosis vary depending on the treatment that a person is under and how much the disease has progressed. Once a person is exposed to the bacteria, the infection is categorized into three forms: latent Tuberculosis infection, active Tuberculosis, and multi-drug resistant tuberculosis. A person with latent Tuberculosis has an immune system that is competent to prevent the spread and keep Mtb to remain in its dormant form. A person with active tuberculosis is capable of spreading the bacteria to others and begins to display common symptoms. Mtb begins to grow and infect mainly lungs and possibly spread to other extrapulmonary parts of the body(6). Active tuberculosis can be treated by taking antibiotics for several months even though it is more preferable to get treatment during latent TB infection. Once a person fails to take medications or get treatments consistently until Tuberculosis is completely cured, it can develop into a more severe form, known as multi-drug resistant tuberculosis (MDR-TB). MDR-TB develops as the bacteria becomes resistant to the antibiotics that it has already encountered, which could ultimately lead to death unless taken alternate medications or treatment(8).

A person with active pulmonary Tuberculosis can simply release the bacteria into the air and infect others by exhaling, coughing, spitting, laughing, etc. When Mycobacterium tuberculosis enters a healthy person, symptoms may not readily appear since the immune system is strong enough to prevent the bacteria from spreading throughout the body (bacteria is still alive but not spreading). On the other hand, others are more prone to active tuberculosis if they:

•are living in contact with someone that has active Tuberculosis

•are nurses or doctors whom are taking care of patients with active Tuberculosis

•have weak immune system from having illness (such as HIV)

•do not have healthcare/ treatment available to cure or prevent the bacteria from spreading

Once a person has active Tuberculosis, they will display common symptoms such as sweating/fever, fatigue, consistent coughing for a significant period of time, and difficulty in breathing(7).

Why is this disease a problem in [India]

Tuberculosis became prevalent, starting in the 1950s and continued to threaten the population in India affecting two out of five people. It is also known as the “disease of the poor” because it is commonly spread amongst people living in overcrowded and underprivileged areas. Although Tuberculosis is problematic world-wide, it is considered more deadly in India because emerging cases of muti-drug resistant Tuberculosis which results in high percentage of death. MDR-TB develops more frequently in India because they have insufficient healthcare to ensure that patients are getting treatments that they need. Most patients take antibiotics irregularly or stop taking medications before they are completely treated. In addition, women ignore the symptoms and neglect to get the treatment. Since women take care of the household, they spread the MtB more readily to their children and husbands.

In the last two decades, the spread of HIV in India has increased the vulnerability to Tuberculosis within the population. Comparing people who were HIV+ and HIV-, HIV+ appeared to have 50~60% lifetime risk whereas HIV- had 10% lifetime risk to develop Tuberculosis disease. Regardless of the government’s effort to prevent the spread of Tuberculosis, India has become one of the “highest Tuberculosis burdened country” by presenting one-fifth of the entire global Tuberculosis cases.

What is being done to address this problem

Today in India more than 250,000 people die from tuberculosis every year(6). The most common treatment for Tuberculosis involves the prescription of one or more of the six antibiotics (pyrazinamide which inhibits fatty acid synthesis, isoniazid which inhibits mycolic acid synthesis, cycloserine or ethambutol which inhibit cell wall biosynthesis, capreomycin which inhibits the bacterium’s peptide synthesis, or rifampicin which acts on RNA polymerase) for the long term, usually between six months to three years. Even though these anti-tuberculosis medications have been available for decades now, death rates and incidences of the infectious disease have not been declining significantly in India. For this reason, a government supported program called DOTS has been implemented in the regions of the country since 1993, and since 2006 has been extended to provide coverage to all of India’s population of more than one billion people. The strategy of DOTS or the Directly Observed Treatment, Short-course program (or Revised National Tuberculosis Control Programme as it is known in India) is to provide plentiful medication and supervised care to all those infected with the disease(7). All affected individuals are guaranteed the necessary amount of the top anti-tuberculosis drugs for the whole course of treatment. Furthermore, the affected individuals are supervised to ensure the proper intake of the medicine. Under the program, any individual can be screened for the disease free of charge (7). Today, the success rate of the program is 85%, meaning that 85% of all those who receive(d) treatment are no longer infected with Tuberculosis(8). Though the program has shown significant success in treating and diagnosing emerging cases of the disease, Tuberculosis is still a major problem in India as is evident by the appearance of drug resistant tuberculosis because patients do not complete the medication treatment for the prescribed term due to the economic hardships(8). It would be fair to say that with improved quality of life more affected individuals would be able to complete the advised anti-tuberculosis treatment, since most of those affected live in poverty.

What else could be done to address this problem

Currently, a number of studies and advancements are being done to resolve the situation in India. Researchers have determined that the most common Mycobacterium tuberculosis strains are the Central-Asian Clade in Northern India and the East-African-Indian Clade in Southern India (9). Understanding the genetic similarities and differences between these two strains in comparison to other tuberculosis strains helps build vaccinations more specific to the cause in India. Targeting regions unique to certain Indian strains, such as the TbD1 region which is only found in the East-African-Indian Clade, may help in creating a vaccine with greater specificity. One of the more common vaccines against tuberculosis is bacillus Calmette-Guérin, a live but weakened strain of bovine tuberculosis bacillus. Though widely used throughout the world, this vaccine only shows an efficacy rate of about 50% (10). New, more effective treatments are being researched to identify more common extracellular proteins displayed by infected host cells. Identifying these key proteins further assists in targeting key markers for vaccines. Additionally, researchers are using other means to conduct research on tuberculosis resistance and vaccination. The use of animal models, such as mice and rabbits, helps test new vaccines and treatments as these and other species share many physiological commonalities with humans (11). Though testing with these species does not give exact results as testing within a human population, the methods are generally more cost efficient and safer for humans while still producing useful results. Further research in the specific strains in India as well as the use of animal models will progress science forward into creating a more tuberculosis preventive India.

References

1. American Lung Association. http://www.lungusa.org/site/apps/nlnet/content3.aspx?c=dvLUK9O0E&b=2060731&content_id={50031760-2D7C-4FFF-AD75-4C49BDD1CD7D}&notoc=1&gclid=CPamgJK9v5wCFRxNagodKkC_ng

2. 2009 Kenneth Todar, PhD.Todar's Online Textbook of Bacteriology http://www.textbookofbacteriology.net/tuberculosis.html

3.http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=14663145 Shimono, Nobuyuki; Morici, Lisa; Casali, Nicola; Cantrell, Sally; Sidders, Ben; Ehrt, Sabine; and Riley, Lee W. “ Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mcel operon.” Proc Natl Acad Sci U S A. 2003. 100(26): 15918-15923.

4. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=387609&tool=pmcentrez Tan, Yi-Wei; Meng, Shufang; Li, Haijing; and Stratton, Charles W. “PCR enhances Acid-Fast Bacillus Stain-Based Rapid Detection of Mycobacterium tuberculosis.” J Clin Microbiol. 2004. 42(4): 1849-1850.

5. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15939785 Kaufmann, Stefan H.E.; Cole, Stewart T.; Mizrahi, Valerie; Rubin, Eric; and Nathan, Carl. “Mycobacterium tuberculosis and the host response.” J Exp Med. 2005. 201(11): 1693-1697.

6. Griffith D, Kerr C (1996). "Tuberculosis: disease of the past, disease of the present". Journal of Perianesthesia Nursing, Volume 11 issue 4: P 240–5.

7. Ministry of Health and Family Welfare. TB India 2007, RNTCP status report. (Accessed August 18, 2009) http://www.tbcindia.org/pdfs/TB%20India%202007.pdf

8. World Health Organization (WHO). "Global and regional incidence", Tuberculosis Fact sheet N°104, WHO, March 2006, (accessed August 20,2009). http://www.who.int/mediacentre/factsheets/fs104/en/index.html

9. World Health Organization: Epidemiology of TB in the Region (South-East Asia) http://www.searo.who.int/en/Section10/Section2097/Section2100_10639.htm

10. TBC India: Directorate General of Health Services, Ministry of Health and Family Welfare: About RNTCP. http://www.tbcindia.org/RNTCP.asp

11. Khatri, G. R., and Thomas R. Frieden. "Controlling Tuberculosis in India." The New England Journal of Medicine 347.18 (2002): 14211427.Web.<http://content.nejm.org/cgi/content/full/347/18/1420

12.Arora J, Singh UB, Suresh N, Rana T, Porwal C, Kaushik A, Pande JN. "Characterization of predominant Mycobacterium tuberculosis strains from different subpopulations of India." Infection, Genetics and Evolution (2009): 832-839.

13.Horwitz MA, Harth G, Dillon BJ, Maslesa-Galic' S. "Recombinant bacillus calmette-guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model." Proceedings of the National Academy of Sciences of the U.S.A. (2000): 13853-8.

14.U.D. Gupta, V.M. Katoch. "Animal models of tuberculosis for vaccine development." Indian Journal of Medical Research (2009): 11-18.

Edited by [Alexander Abejar, Yekaterina Tarasova, Kimya Panah, Jeung Lee, Huyen Htdao], students of Rachel Larsen