Mycobacterium tuberculosis
Mycobacterium tuberculosis (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis.[1][2] First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive.[3] Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.[2][4]
This article is about the bacterium. For the infection, see Tuberculosis.Genome[edit]
The genome of the H37Rv strain was published in 1998.[44][45] Its size is 4 million base pairs, with 3,959 genes; 40% of these genes have had their function characterized, with possible function postulated for another 44%. Within the genome are also six pseudogenes.
Fatty acid metabolism. The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating the waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival. Furthermore, experimental studies have since validated the importance of a lipid metabolism for M. tuberculosis, consisting entirely of host-derived lipids such as fats and cholesterol. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates.[46] M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis, especially during the chronic phase of infection when other nutrients are likely not available.[47]
PE/PPE gene families. About 10% of the coding capacity is taken up by the PE/PPE gene families that encode acidic, glycine-rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.[48]
Noncoding RNAs. Nine noncoding sRNAs have been characterised in M. tuberculosis,[49] with a further 56 predicted in a bioinformatics screen.[50]
Antibiotic resistance genes. In 2013, a study on the genome of several sensitive, ultraresistant, and multiresistant M. tuberculosis strains was made to study antibiotic resistance mechanisms. Results reveal new relationships and drug resistance genes not previously associated and suggest some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role of the intergenic regions in the development of this resistance, and most of the genes proposed in this study to be responsible for drug resistance have an essential role in the development of M. tuberculosis.[51]
Epigenome. Single-molecule real-time sequencing and subsequent bioinformatic analysis has identified three DNA methyltransferases in M. tuberculosis, Mycobacterial Adenine Methyltransferases A (MamA),[52] B (MamB),[53] and C (MamC).[54] All three are adenine methyltransferases, and each are functional in some clinical strains of M. tuberculosisand not in others.[55][54] Unlike DNA methyltransferases in most bacteria, which invariably methylate the adenines at their targeted sequence,[56] some strains of M. tuberculosis carry mutations in MamA that cause partial methylation of targeted adenine bases.[54] This occurs as intracellular stochastic methylation, where a some targeted adenine bases on a given DNA molecule are methylated while others remain unmethylated.[54][57] MamA mutations causing intercellular mosaic methylation are most common in the globally successful Beijing sublineage of M. tuberculosis.[54] Due to the influence of methylation on gene expression at some locations in the genome,[52] it has been hypothesized that IMM may give rise to phenotypic diversity, and partially responsible for the global success of Beijing sublineage.[54]
Host genetics[edit]
The nature of the host-pathogen interaction between humans and M. tuberculosis is considered to have a genetic component. A group of rare disorders called Mendelian susceptibility to mycobacterial diseases was observed in a subset of individuals with a genetic defect that results in increased susceptibility to mycobacterial infection.[83]
Early case and twin studies have indicated that genetic components are important in host susceptibility to M. tuberculosis. Recent genome-wide association studies (GWAS) have identified three genetic risk loci, including at positions 11p13 and 18q11.[84][85] As is common in GWAS, the variants discovered have moderate effect sizes.
DNA repair[edit]
As an intracellular pathogen, M. tuberculosis is exposed to a variety of DNA-damaging assaults, primarily from host-generated antimicrobial toxic radicals. Exposure to reactive oxygen species and/or reactive nitrogen species causes different types of DNA damage including oxidation, depurination, methylation, and deamination that can give rise to single- and double-strand breaks (DSBs).
DnaE2 polymerase is upregulated in M. tuberculosis by several DNA-damaging agents, as well as during infection of mice.[86] Loss of this DNA polymerase reduces the virulence of M. tuberculosis in mice.[86] DnaE2 is an error-prone DNA repair polymerase that appears to contribute to M. tuberculosis survival during infection.
The two major pathways employed in repair of DSBs are homologous recombinational repair (HR) and nonhomologous end joining (NHEJ). Macrophage-internalized M. tuberculosis is able to persist if either of these pathways is defective, but is attenuated when both pathways are defective.[87] This indicates that intracellular exposure of M. tuberculosis to reactive oxygen and/or reactive nitrogen species results in the formation of DSBs that are repaired by HR or NHEJ.[87] However deficiency of DSB repair does not appear to impair M. tuberculosis virulence in animal models.[88]
Vaccine[edit]
The BCG vaccine (bacille Calmette-Guerin), which was derived from M. bovis, while effective against childhood and severe forms of tuberculosis, has limited success in preventing the most common form of the disease today, adult pulmonary tuberculosis.[92] Because of this, it is primarily used in high tuberculosis incidence regions, and is not a recommended vaccine in the United States due to the low risk of infection. To receive this vaccine in the United States, an individual is required to go through a consultation process with an expert in M. tuberculosis and is only given to those who meet the specific criteria.[93]
Research indicates there may be a correlation between BCG vaccination and better immune response to COVID-19.[94]
The DNA vaccine can be used alone or in combination with BCG. DNA vaccines have enough potential to be used with TB treatment and reduce the treatment time in future.[95]