Mycobacterium tuberculosis, the pathogen bacterium that is with us since we left Africa
Tuberculosis and its agent
Tuberculosis is a common and often deadly infectious disease if left untreated, caused by mycobacteria, mainly Mycobacterium tuberculosis. Mycobacteria such as M. tuberculosis and M. leprae (the leprosy) are considered as gram-positive bacteria because they have glycopeptides, but they are not stained with crystal violet, because outside of glycopeptide they have a good layer of fat, called the mycolic acid (Figure 1). Precisely the prefix “myco” comes from the fungic appearance on the surface of liquid cultures of these mycobacteria.
Figure 1. Mycobacterium tuberculosis with his particular cell wall, and the more used antibiotics against this bacterium. (Figure from National Institute of Allergy and Infectious Diseases)
This mycobacterium was discovered as causing tuberculosis by the German Robert Koch (1882) and for this reason, it is also called Koch’s bacillus. It is a strict aerobic bacterium, since it needs high levels of oxygen, and therefore mostly infects the lungs. It has a generation time of about 15-20 hours, so it has a very slow growing compared to other bacteria (remember the 20 minutes in Escherichia coli). From a taxonomic point of view they are Actinobacteria, or gram-positive of high G+ C, as corynebacteria or Actinomycetales.
The virulence of M. tuberculosis is very complex and has many facets (Todar K.). Although apparently it produces no toxin, it has a large repertoire of physiological and structural properties that explain its virulence and pathology of tuberculosis. Once in the lungs, the bacteria are captured by alveolar macrophages, but they cannot be digested due to the structure of the bacterial cell wall and because bacteria neutralize reactive compounds from macrophages. The mycolic acid also makes the cell not permeable to lysozyme. M. tuberculosis can grow intracellularly without being affected by the immune system, and at the same time, it secretes several proteins involved in the pathogenesis. For instance, the antigen 85 complex, which binds fibronectin, facilitates the formation of tubercles in the lungs (Figure 2).
Figure 2. Progress of infection by M. tuberculosis in the lungs, with the formation of tubercles (From humanorgans.org/tuberculosis)
Tuberculosis usually attacks the lungs but can also affect many other organs. The classic symptoms of tuberculosis are a chronic cough with bloody sputum, fever and other symptoms. The diagnosis relies on radiology of the thorax, a tuberculin skin test and blood analysis, and a microscopic examination and microbiological culture of body fluids. The treatment of tuberculosis is difficult and requires long treatment with various antibiotics. The most commonly used are rifampicin and isoniazid (Figure 1). However, antibiotic resistance is a growing problem in some types of tuberculosis. Prevention is based mainly on vaccination, usually with the Bacillus Calmette-Guérin vaccine (BCG).
Tuberculosis is transmitted by air when infected people cough, sneeze or spit. One third of the world’s current population is infected with M. tuberculosis, and there is a new infected person every second. However, in most of these cases the disease is not fully developed, as the latent and asymptomatic infections are the most common. Approximately one in ten latent infections eventually it progress to active disease, which, if left untreated, kills more than half of the victims. In one year (2004), the global statistics included 14.6 million chronic active cases, 8.9 million new cases and 1.6 million deaths, mostly in developing countries. In addition, a growing number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or AIDS.
When the human tuberculosis originated ?
The origin of the population infectious diseases (such as plague, cholera, etc.), id est., those that spread easily where there are many humans together, has been associated with the Neolithic demographic transition, about 10,000 years ago, when the revolution of agriculture allowed the establishment of the first sedentary villages, with numbers of humans living together. Many of these diseases are associated with other animals, from which they are transmitted to humans. Until recently it was believed that tuberculosis was of this type, having also led the Neolithic, but in fact the majority of tuberculosis have no relationship with other animals.
However, a recent study (Comas et al. 2013) provides data in the sense that the disease originated long before, more than 70,000 years ago, going with the modern humans out of Africa and spreading to the world. Effectively, this work of 22 co-authors from 9 countries (and the first author of which is the young Valencian Iñaki Comas) have analyzed and compared the genomes of 259 strains of the complex M. tuberculosis to see their evolutionary history. In doing so, within the 4.4 Mb genome of this species the authors have identified 34,167 SNPs polymorphic sites, i.e., sites of DNA that have some different nucleotide in function of strains, and with which they have been able to reconstruct the phylogeny of this bacterium. In this way, they have confirmed seven lineages (groups of strains) that had been suggested by other techniques. The most interesting thing is that this phylogeny of genomes of M. tuberculosis is very similar to the human mitochondrial genome phylogeny, as shown in Figure 3. Therefore, this suggests that the evolution of tuberculosis bacteria goes parallel to that of modern humans.
Figure 3. The phylogeny of genomes from 220 strains of M. tuberculosis, with the different lineages (MTBC, left), is similar to that of mitochondrial genomes (right) of 4995 humans, with their main haplogroups (from Comas et al. 2013, Fig. 1 c, d).
Based on these phylogenies and on the frequencies of mutations observed in the genomes of M. tuberculosis, the origin of the different lineages of this bacterium has been established, calculating at what time of the human Palaeolithic the different branches were appearing, from approx. 73,000 to 42,000 years (Figure 4), which, having seen the parallel with mitochondrial DNA, coincide with the proposed dates of the modern humans expansion from Africa to Eurasia.
Figure 4. Expansion of complex M. tuberculosis going out of Africa, with the origin of different lineages and the approximate data (thousands years) of the evolutionary branches (from Comas et al. 2013, Fig. 2a).
Therefore, we can conclude that tuberculosis and its bacterial agent has been a constant companion of the modern humans during their evolution and their global spread, at least in the last 70,000 years, and also that the bacterium M. tuberculosis has been able to adapt to changes in human population. In addition, in this regard last years an increase in resistant strains to multiple antibiotics has been observed. The study of these mechanisms of bacterial adaptation may help to predict future patterns of disease and to design rational strategies to fight it.
Comas, Iñaki, et al. (2013) Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nature Genetics 45, 1176-1182.
Todar K., Todar’s Online Textbook of Bacteriology.
Mycobacterium tuberculosis in wikipedia: http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis
Tuberculosis in viquipèdia (Catalan): http://ca.wikipedia.org/wiki/Tuberculosi.