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Mycobacteria

 Mycobacteria are immobile, slow-growing rod-shaped, gram-positive bacteria with high genomic G+C content (61-71%). Due to their special staining characteristics under the microscope, which is mediated by mycolic adic in the cell wall, they are called acid-fast. This is also the reason for the hardiness of mycobacteria.

Mycobacteria can be divided into three groups:

  • Mycobacterium tuberculosis complex – causative pathogen of tuberculosis
  • Nontuberculous mycobacteria (NTM)
  • Mycobacterium leprae – causative pathogen of leprosy 

Mycobacterium tuberculosis complex

The pathogens that cause tuberculosis are mycobacteria that belong to the M. tuberculosis complex. This complex comprises the following species:

  • M. tuberculosis
  • M. bovis (subsp. bovis and caprae)
  • vaccine strain M. bovis BCG (Bacille Calmette-Guérin)
  • M. africanum
  • M. canettii
  • M. microti
  • M. pinnipedii

These species are, with the exception of M. bovis BCG, considered to cause tuberculosis (TB) in humans and animals. Despite their close genetic similarity, these organisms differ considerably with regard to epidemiology, pathogenicity and their host spectrum.

M. tuberculosis is considered to be the main cause of TB in humans.

In 1882 the German physician and microbiologist Robert Koch discovered M. tuberculosis to be the causative pathogen of phthisis. Based on this discovery, diagnosis of the disease could considerably be improved. Koch published his findings on March 24th 1882 in the Berlin Society of Physiology. Therefore, March 24th is now known to be World Tuberculosis Day, initiated by the World Health Organization (WHO).

Tuberculosis infections usually arise from patients, who suffer from active and thus infectious pulmonary tuberculosis. The pathogens are transmitted via droplet infection through the air by coughing or sneezing. The risk of infection is increased by bad hygiene conditions and in densely populated areas. As the pathogens infect cells of the immune system, so-called macrophages, especially infants and immunocompromised persons are at risk. In most cases the immune system succeeds in fighting the bacteria or in encapsulating them. Mycobacteria can then persist in the body for several years as latent tuberculosis without causing any symptoms. It cannot be predicted when and if reactivation occurs. Even though every organ can be affected, the disease is manifested as pulmonary tuberculosis in 80% of the patients.

M. bovis is the major cause of bovine tuberculosis. It can be transmitted to humans by the consumption of unpasteurised milk or in rare cases via inhalation of dust in barns. Nowadays this infection is quite rare in central Europe as the cattle population is largely free of tuberculosis.
M. bovis can be divided into two subspecies, M. bovis subsp. bovis and M. bovis subsp. caprae. While the latter is sensitive to pyrazinamide (PZA), M. bovis subsp. bovis is resistant.
The BCG vaccine strain, which was developed from M. bovis, is rarely used nowadays in most European countries because its effectiveness is unclear, side effects are frequent and the epidemiologic situation does not require vaccination. Nevertheless, the WHO still recommends BCG vaccination for children under one year of age in high risk countries.

A heterogeneous group of strains that can mainly be found in Africa and which exclusively causes TB in humans, is called M. africanum. M. canettii was mainly isolated from small rodents, whereas M. pinnipedii was detected in seals. On very rare occasions these pathogens were found to cause TB in humans. 
 

Tuberculosis

TB can be found all around the world and other than HIV/AIDS and malaria it is one of the most frequent infectious diseases. Recent estimations suggest that one third of the world’s population is infected with tuberculosis. According to the WHO, each year more than nine million people are newly infected with TB and about two million die from it. About 95% of all newly infected patients live in developing countries. The facts that more and more resistant mycobacteria emerge and that co-infections with HIV are frequent make it even more difficult to fight TB.

There are four important parameters for the containment of TB:

  • Early diagnosis
  • Prevention of disease spreading
  • Effective treatment with antituberculotics
  • Prevention of resistance development
     

Nontuberculous mycobacteria

The group of nontuberculous mycobacteria (NTM), formerly called atypical or ubiquitous mycobacteria, contains over 150 species. NTM can be found ubiquitously in nature and show a broad diversity regarding where they can be found and how they adapted to certain environmental conditions. They can be detected in soil, ground and drinking water as well as in food like pasteurized milk or cheese. In general, NTM are less pathogenic. Nevertheless, they can cause illness in humans, especially in immunocompromised persons or those who suffer from previous pulmonary diseases.

The M. avium complex (MAC) comprises the species M. avium and M. intracellulare that range among the most important and most frequent pathogenic NTM. Just like M. kansasii, M. malmoense and M. xenopi they mostly cause pulmonary infections. M. marinum is responsible for skin and soft tissue infections like aquarium granuloma. Typically patients got in contact with an aquarium.

Diagnostics of NTM is often difficult. The decision if an infection requires treatment can only be made when the same pathogen is detected in different samples from one patient.

NTM can be cultivated on common liquid and solid culture media. According to their growth rate and production of pigments, they are classified into 4 groups (RUNYON classification):
Group I: photochromogen (strains producing pigments under the influence of light), slow-growing NTM (e.g.  M. kansasii, M. marinum)
Group II: skotochromogen (strains producing pigments even in the dark), slow-growing NTM (e.g. M. scrofulaceum, M. gordonae)
Group III: non-chromogen (strains do not produce pigments), slow-growing NTM (e.g. M. avium, M. haemophilum)
Group IV: rapid-growing NTM (e.g. M. abscessus, M. chelonae)

Currently NTM are classified according to their growth rate and are divided into slow-growing (SGM) and rapid-growing (RGM) mycobacteria. They belong to the RGM group if under ideal conditions they grow within less than seven days and to the SGM group if they need more than seven days to grow.

There is no standard therapy for the treatment of NTM infections. Therapy always depends on the respective species and its resistances to antibiotics.

In the last decades an increase in the number of NTM infections could be observed worldwide, but especially in countries with low tuberculosis prevalence. Therefore, reliable diagnostics provide the basis for successful therapy.
 

Leprosy

Leprosy is a chronic infectious disease that is caused by Mycobacterium leprae. The bacterium (“Hansen’s bacillus”) was first described in 1873 by the Norwegian physician Gerhard H. Armauer Hansen. Due to its slow proliferation rate with a generation time of 10 to 14 days, the incubation period can last several months or even years. To become infected one must be in close contact with a patient. Even though the exact mechanism of transmission is unclear, droplet infection is suspected. Only 5% of all people can develop leprosy, the rest is genetically immune. Nevertheless they can become carriers and infect someone else.

Most leprosy infections are without pathological findings and heal spontaneously. According to WHO guidelines leprosy can be divided into paucibacillary (tuberculoid) and multibacillary (lepromatous) leprosy. The former progresses slowly and can easily be treated. The latter more infectious form is characterised by a quick progression of the disease due to strongly proliferating bacteria and manifests itself with ulcers on hands, feet, ears or in the face.

In general, leprosy is curable. Nevertheless, if the disease is diagnosed too late, nerve tracts can be irreversibly damaged. As leprosy can be treated it is nearly extinct in countries that provide good health care. In contrast, in many developing countries the disease is still a serious health problem. People who suffer from leprosy are also facing social problems that go hand in hand with the disease. Additionally, treatment is getting more difficult as antibiotic resistances became more and more frequent in recent years.

Leprosy is diagnosed according to the clinical symptoms and by laboratory diagnostics. Unfortunately, M. leprae cannot be cultivated like other mycobacteria. Culture and resistance testing is only successful in animal models and takes about one year. Also microscopic diagnostics of skin or nasal smears is often difficult as samples are false-negative in 70% of all cases. Therefore, the detection of bacterial DNA in skin smears using PCR is usually the method of choice.

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