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Part II, Nobody does it better: Mycobacterium tuberculosis and persistence

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“Tuberculosis will not be eliminated anywhere until it is eliminated everywhere.”
--Don Enarson
Strategies for the fight against tuberculosis. Pneumologie 1994; 48: 140–43.

Since tuberculosis first plagued mankind, it has continued to wreak illness and death worldwide. In 1882, Professor Robert Koch determined that TB is caused by tubercle bacilli. Shortly after the discovery of the tubercle bacillus, investigators noted the persistence of the bacteria in what appeared to be normal tissue. A time jump to 1944 offered the discovery of the antibiotic streptomycin, the first of a class of drugs to cure TB. The antibiotic isoniazid was discovered in 1952, and more drugs have since followed. The 1980s ushered in a dramatic increase in the number of TB cases, primarily attributed to the spread of the human immunodeficiency virus (HIV) as well as more drug-resistant TB strains. If an antibiotic does not kill all of the targeted bacteria, the survivors and their descendants become resistant to the drug and often to other antibiotics. In 1993, the World Health Organization (WHO) gave TB the status of a global emergency.

The course of human TB infection can vary widely. Some people apparently do not become infected even when exposed long-term to others with TB disease. In these cases, the tuberculin skin (purified protein derivative or PPD) tuberculin test is negative along with a negative Interferon-gamma (IFN-%) Release Assay (IGRA). In the majority of people, the initial infection is subdued by a cell-mediated immune response, and most individuals will not develop symptoms. About ten percent of those infected will go on to clinical disease. The risk of disease is greater with a weakened immune system.

In about 5% of infected individuals who do not develop symptoms, a viable population of mycobacteria will be retained, which may be dormant for many years—latent TB infection (LTBI). The LTBI may be identified by calcification (granuloma or tubercle) in the lung or regional lymph nodes as shown radiographically. Others with LTBI will develop active disease within a year of infection, and another 5% will have reactivation of the latent infection years from the time of the primary infection, or have subsequent reinfection. The host state of immunity greatly influences the risk of disease, and all the factors affecting the progression of infection to disease remain elusive.

How does M. tuberculosis survive despite a host immune response? One hypothesis is the bacteria, especially those in tubercles, are hidden from immune system surveillance. Alternatively, the bacteria actively subvert the local immune response by interfering with cell signaling. It is possible that non-replicating bacteria develop a type of phenotypic tolerance to cell-mediated immunity, resulting from bacterial stress-induced responses or metabolic changes. Another theory suggests in the face of chronic immune activation, finally the immune response shuts down, or perhaps persistent infection at a low level benefits the host by stimulating immunological memory.

Several strategies to reduce the TB scourge are now available, or in the offing and include: 1) Rapid diagnosis of persons with active TB and early treatment; epidemiologic estimates suggest that individuals with untreated TB disease can infect an average of 10 to 15 people every year; thus, the search for new and rapid diagnostic methods is a priority. 2) The detection and treatment of latent TB—unlike individuals with active TB, latently infected persons are not infectious; however, this carrier population is at the highest risk of progressing to TB disease, and screening for these individuals has become an important approach in the plan to control global TB. 3) Prophylactic vaccination-- Bacillus Calmette–Guérin (or Bacille Calmette–Guérin, BCG) is the only current and most widely used vaccine against tuberculosis. However, in children more than five years old, protection becomes variable, and generally, BCG should not be given to HIV-infected children because of the risk of disseminated TB disease from BCG. The need for a better vaccine is critical to an effective TB program, and some TB vaccine candidates are in clinical trials.

Next, we hear from the experts.

References and Read-more-about-it:
1. Kimball’s Biology Pages; Cell-mediated immunity; Available at: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CMI.html; Accessed 04 January 2013.
2. Druszczynska M., Kowalewicz-Kulbat M. et al. Latent M. tuberculosis infection –pathogenesis, diagnosis, treatment and prevention strategies. Polish Journal of Microbiology 2012; 61(1):3-10.
3. Leung AN. Pulmonary tuberculosis: the essentials. Radiology 1999; 210:302-322.
4. Stewart GR, Robertson BD, Young DB. Tuberculosis: a problem with persistence. Nature Reviews Microbiology. 2003; 1:97-105.
5. Barry 3rd CE, Boshoff HI, Dartois V et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nature Reviews Microbiology. 2009; 7:845-855.

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