Mycobacterium tuberculosis

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novel, promising therapeutic target is mycobacterial membrane protein large 3 (MmpL3). The mycobacterial membrane protein large (MmpL) proteins are transmembrane proteins which play a key role in the synthesis of the cell wall and the transport of the associated lipids. Of these, MmpL3 is essential; knock-out of which has been shown to be bactericidal. Due to its essential nature, MmpL3 inhibitors show promise as alternative therapeutic measures in the age of antibiotic resistance. Inhibition of MmpL3 function showed an inability to transport trehalose monomycolate - an essential cell wall lipid - across the plasma membrane. The recently reported structure of MmpL3 revealed resistance-conferring mutations to associate primarily with the transmembrane domain. Although resistance to pre-clinical MmpL3 inhibitors has been detected, analysis of the widespread mutational landscape revealed a low level of environmental resistance. This suggests that MmpL3 inhibitors currently undergoing clinical trials would face little resistance if made available. Additionally, the ability of many MmpL3 inhibitors to work synergistically with other antitubercular drugs presents a ray of hope in combatting the TB crisis.

452: 489: 1540:. MDR is associated with a relatively poor treatment success rate of 52%. Isoniazid and rifampin resistance are tightly linked, with 78% of the reported rifampin-resistant TB cases in 2019 being resistant to isoniazid as well. Rifampin-resistance is primarily due to resistance-conferring mutations in the rifampin-resistance determining region (RRDR) within the rpoB gene. The most frequently observed mutations of the codons in RRDR are 531, 526 and 516. However, alternative more elusive resistance-conferring mutations have been detected. Isoniazid function occurs through the inhibition of mycolic acid synthesis through the NADH-dependent enoyl-acyl carrier protein (ACP)-reductase. This is encoded by the 1477:, only two are truly global in their distribution: Lineages 2 and 4. Among these, Lineage 4 is the most well dispersed, and almost totally dominates in the Americas. Lineage 4 was shown to have evolved in or in the vicinity of Europe, and to have spread globally with Europeans starting around the 13th century. This study also found that Lineage 4 tuberculosis spread to the Americas shortly after the European discovery of the continent in 1492, and suggests that this represented the first introduction of human TB on the continent (although animal strains have been found in human remains predating Columbus. Similarly, Lineage 4 was found to have spread from Europe to Africa during the 1021: 1032: 34: 97: 225: 6244: 403: 76: 1410:, like humans, evolved in Africa and subsequently spread with anatomically modern humans out of Africa across the world. By calibrating the mutation rate of M. tuberculosis to match this narrative, the study suggested that MTBC evolved 40,000–70,000 years ago. Applying this time scale, the study found that the 1548:

becomes increasingly common, the emergence of pre-extensively drug resistant (pre-XDR) and extensively drug resistant (XDR-) TB threatens to exacerbate the public health crisis. XDR-TB is characterised by resistance to both rifampin and Isoniazid, as well second-line fluoroquinolones and at least one

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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. Because of this, it is primarily used in high tuberculosis incidence regions, and is not a recommended vaccine in the United

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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

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is its unique cell wall. Saturated with long-chain fatty acids or mycolic acids, the mycobacterial cell presents a robust, relatively insoluble barrier. This has led to its synthesis being the target of many antibiotics - such as Isoniazid. However, resistance has emerged to the majority of them. A

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carry mutations in MamA that cause partial methylation of targeted adenine bases. This occurs as intracellular stochastic methylation, where a some targeted adenine bases on a given DNA molecule are methylated while others remain unmethylated. MamA mutations causing intercellular mosaic methylation

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was able to adapt to changing human populations and that the historical success of this pathogen was driven at least in part by dramatic increases in human host population density. It has also been demonstrated that after emigrating from one continent to another, a human host's region of origin is

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poses an increasing threat to global public health. In 2019, the WHO reported the estimated incidence of antibiotic resistant TB to be 3.4% in new cases, and 18% in previously treated cases. Geographical discrepancies exist in the incidence rates of drug-resistant TB. Countries facing the highest

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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

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Typing of strains is useful in the investigation of tuberculosis outbreaks, because it gives the investigator evidence for or against transmission from person to person. Consider the situation where person A has tuberculosis and believes he acquired it from person B. If the bacteria isolated from

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levels were found to be upregulated, and this, in turn, would impact the normal apoptotic response of macrophages to clear pathogens, as PPM1A is involved in the intrinsic and extrinsic apoptotic pathways. Hence, when PPM1A levels were increased, the expression of it inhibits the two apoptotic

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are noted. The first scheme, called exact tandem repeat, used only five loci, but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called mycobacterial interspersed repetitive unit, had discrimination as good as PFGE. The third generation (mycobacterial

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Lineages 2, 3 and 4 all share a unique deletion event (tbD1) and thus form a monophyletic group. Types 5 and 6 are closely related to the animal strains of MTBC, which do not normally infect humans. Lineage 3 has been divided into two clades: CAS-Kili (found in

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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.

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JNK plays a key role in the control of apoptotic pathways—intrinsic and extrinsic. In addition, it is also found to be a substrate of PPM1A activity, hence the phosphorylation of JNK would cause apoptosis to occur. Since PPM1A levels are elevated during

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complex are all clonal in their spread. The main human-infecting species have been classified into seven lineages. Translating these lineages into the terminology used for spoligotyping, a very crude genotyping methodology, lineage 1 contains the

884:, organized aggregates of immune cells, are a hallmark feature of tuberculosis infection. Granulomas play dual roles during infection: they regulate the immune response and minimize tissue damage, but also can aid in the expansion of infection. 1071:

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

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Due to the influence of methylation on gene expression at some locations in the genome, it has been hypothesized that IMM may give rise to phenotypic diversity, and partially responsible for the global success of Beijing sublineage.

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are used. Cells are curved rod-shaped and are often seen wrapped together, due to the presence of fatty acids in the cell wall that stick together. This appearance is referred to as cording, like strands of cord that make up a rope.

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each person belong to different types, then transmission from B to A is definitively disproven; however, if the bacteria are the same strain, then this supports (but does not definitively prove) the hypothesis that B infected A.

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Zhang H, Li D, Zhao L, Fleming J, Lin N, Wang T, et al. (October 2013). "Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance".

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sequences from Hungarian mummies more than 200 years old. In total, the evidence thus favors this more recent estimate of the age of the MTBC most recent common ancestor, and thus that the global evolution and dispersal of

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complex were 40,000 to 70,000 years old, this would necessitate an evolutionary rate much lower than any estimates produced by genomic analyses of heterochronous samples, suggesting a far more recent common ancestor of the

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strain was published in 1998. 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

2214:"Molecular detection and identification of mycobacterium tuberculosis complex and four clinically important nontuberculous mycobacterial species in smear-negative clinical samples by the genotype mycobacteria direct test" 3425:"Mycobacterial interspersed repetitive unit typing of Mycobacterium tuberculosis compared to IS6110-based restriction fragment length polymorphism analysis for investigation of apparently clustered cases of tuberculosis" 1012:

is considered to be multidrug-resistant (MDR TB) if it has developed drug resistance to both rifampicin and isoniazid, which are the most important antibiotics used in treatment. Additionally, extensively drug-resistant

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rates of ABR TB China, India, Russia, and South Africa. Recent trends reveal an increase in drug-resistant cases in a number of regions, with Papua New Guinea, Singapore, and Australia undergoing significant increases.

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Phelan J, de Sessions PF, Tientcheu L, Perdigao J, Machado D, Hasan R, et al. (January 2018). "Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally".

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was found to be a downstream effector that PPM1A has a part to play in, and the apoptotic pathway in macrophages are controlled in this manner. As a result of having apoptosis being suppressed, it provides

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have developed resistance to more than one TB drug, due to mutations in their genes. In addition, pre-existing first-line TB drugs such as rifampicin and streptomycin have decreased efficiency in clearing

1577:. Recent genome-wide association studies (GWAS) have identified three genetic risk loci, including at positions 11p13 and 18q11. As is common in GWAS, the variants discovered have moderate effect sizes. 6323: 1076:, 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. 1544:

gene. As a result, isoniazid resistance is primarily due to mutations within inhA and the KatG gene or its promoter region - a catalase peroxidase which is required to activate Isoniazid. As MDR in

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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

1017:(XDR TB) is characterized by resistance to both isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). 1670:

has existed throughout history, but the name has changed frequently over time. In 1720, though, the history of tuberculosis started to take shape into what is known of it today; as the physician

451: 7130: 938:-infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche. thus decreasing the treatment times for 997:

interspersed repetitive unit – 2) added a further nine loci to bring the total to 24. This provides a degree of resolution greater than PFGE and is currently the standard for typing

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to reactive oxygen and/or reactive nitrogen species results in the formation of DSBs that are repaired by HR or NHEJ. However deficiency of DSB repair does not appear to impair

5906:"Either non-homologous ends joining or homologous recombination is required to repair double-strand breaks in the genome of macrophage-internalized Mycobacterium tuberculosis" 6316: 2091:"Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease" 1102:

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.

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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

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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.

927:-infected macrophages by restoring its normal apoptotic function in defence of pathogens. By targeting the PPM1A-JNK signalling axis pathway, then, it could eliminate 1084:

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

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DNA sequences to formally assess the correlation between them, concluded that they are not congruent. Also, a more recent study which included genome sequences from

7104: 1336:. A seventh type has been isolated from the Horn of Africa. The other species of this complex belong to a number of spoligotypes and do not normally infect humans. 6167: 957:

also has the potential of spreading to other parts of the body. This can cause blood in urine if the kidneys are affected, and back pain if the spine is affected.

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Lineage 4 is also known as the Euro-American lineage. Subtypes within this type include Latin American Mediterranean, Uganda I, Uganda II, Haarlem, X, and Congo.

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group, they undergo recombination with other species. The majority of the known strains of this group have been isolated from the Horn of Africa. The ancestor of

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is able to persist if either of these pathways is defective, but is attenuated when both pathways are defective. This indicates that intracellular exposure of

5330:"Trends in burden of multidrug-resistant tuberculosis in countries, regions, and worldwide from 1990 to 2017: results from the Global Burden of Disease study" 6774: 4766:

Loiseau C, Menardo F, Aseffa A, Hailu E, Gumi B, Ameni G, Berg S, Rigouts L, Robbe-Austerman S, Zinsstag J, Gagneux S, Brites D (2020) An African origin for

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Modlin SJ, Conkle-Gutierrez D, Kim C, Mitchell SN, Morrissey C, Weinrick BC, et al. (October 2020). Stallings CL, Soldati-Favre D, Casadesús J (eds.).

6769: 3914:"Identification of 17 Pseudomonas aeruginosa sRNAs and prediction of sRNA-encoding genes in 10 diverse pathogens using the bioinformatic tool sRNAPredict2" 6016: 3474:"Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis" 488: 7078: 6275: 1001:. However, with regard to archaeological remains, additional evidence may be required because of possible contamination from related soil bacteria. 799:

can be spread by shaking hands, making contact with toilet seats, sharing food or drink, or sharing toothbrushes. However, major spread is through

981:(VNTR), which is technically easier to perform and allows better discrimination between strains. This method makes use of the presence of repeated 845:

prevents maturation of the phagosome. The bacteria also evades macrophage-killing by neutralizing reactive nitrogen intermediates. More recently,

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infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche (M),

5165:"Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean" 6403: 6145: 3248: 5292: 3064: 2190: 2047: 1807:

Fu LM, Fu-Liu CS (1 January 2002). "Is Mycobacterium tuberculosis a closer relative to Gram-positive or Gram-negative bacterial pathogens?".

1791: 1661: 357:. It divides every 18–24 hours. This is extremely slow compared with other bacteria, which tend to have division times measured in minutes ( 5440:"Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis" 4061:"Precision methylome characterization of Mycobacterium tuberculosis complex (MTBC) using PacBio single-molecule real-time (SMRT) technology" 3366:"High-resolution minisatellite-based typing as a portable approach to global analysis of Mycobacterium tuberculosis molecular epidemiology" 1406:

phylogeny to a human mitochondrial genome phylogeny and interpreted these as being highly similar. Based on this, the study suggested that

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typically occurs due to either the accumulation of mutations in the genes targeted by the antibiotic or a change in titration of the drug.

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can contain a gel that emits fluorescent light if mycobacteria are grown. It is distinguished from other mycobacteria by its production of

5965:"Deficiency of double-strand DNA break repair does not impair Mycobacterium tuberculosis virulence in multiple animal models of infection" 7224: 2263:"Identification of mycobacteria in solid-culture media by matrix-assisted laser desorption ionization-time of flight mass spectrometry" 1484:

It has been suggested that ancestral mycobacteria may have infected early hominids in East Africa as early as three million years ago.

6519: 2176: 1399: 1223: 1208: 709: 527: 492: 5704:"Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity" 2759:"Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing" 6612: 6332: 6066: 5306: 3272:"DNA polymorphisms in strains of Mycobacterium tuberculosis analyzed by pulsed-field gel electrophoresis: a tool for epidemiology" 2444: 6587: 2141: 1426:

predictive of which TB lineage they carry, which could reflect either a stable association between host populations and specific

1418: 974: 1257:

clade. These animal strains of MTBC do not strictly deserve species status, as they are all closely related and embedded in the

515: 6939: 5541:

Chalut C (September 2016). "MmpL transporter-mediated export of cell-wall associated lipids and siderophores in mycobacteria".

1109: 4341:"Significance of the identification in the Horn of Africa of an exceptionally deep branching Mycobacterium tuberculosis clade" 3694: 841:); however, this blockade does not prevent fusion of vesicles filled with nutrients. In addition, production of the diterpene 6656: 6646: 6553: 7122: 5251: 1020: 7020: 3240: 2317:"Structome analysis of virulent Mycobacterium tuberculosis, which survives with only 700 ribosomes per 0.1 fl of cytoplasm" 899:. Many secreted and exported proteins are known to be important in pathogenesis. For example, one such virulence factor is 2038:

Fitzgerald DW, Sterline TR, Haas DW (2015). "251 – Mycobacterium tuberculosis". In Bennett JE, Dolin R, Blaser MJ (eds.).

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by several DNA-damaging agents, as well as during infection of mice. Loss of this DNA polymerase reduces the virulence of

978: 7219: 6919: 6764: 6397: 559: 96: 2110: 6905: 6811: 6750: 6676: 1450: 1371: 1359: 469: 5854:"DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis" 5163:

Hershkovitz I, Donoghue HD, Minnikin DE, Besra GS, Lee OY, Gernaey AM, et al. (15 October 2008). Ahmed N (ed.).

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mutants and test individual gene products for specific functions has significantly advanced the understanding of its

4653:"Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis" 7204: 1370:

complex members extracted from three 1,000-year-old Peruvian mummies, came to quite different conclusions. If the

1031: 953:, chest pain when breathing or coughing, weight loss, fatigue, fever, night sweats, chills, and loss of appetite. 7148: 6796: 6580: 6514: 1617: 1461:

evolutionary rate estimated by the Bos et al. study is also supported by a study on Lineage 4 relying on genomic

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complex evolved between 40,000 and 70,000 years ago. However, a later study that included genome sequences from

6933: 6597: 6411: 1613: 1521: 1508: 765: 579: 6012: 4281:"Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes" 1532:

Multidrug-resistant Tuberculosis (MDR-TB) is characterised by resistance to at least the two front-line drugs

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infections, by inhibiting the PPM1A signalling pathways, it could potentially be a therapeutic method to kill

423: 282: 4651:

Eldholm V, Pettersson JH, Brynildsrud OB, Kitchen A, Rasmussen EM, Lillebaek T, et al. (November 2016).

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additional front-line drug. Thus, the development of alternative therapeutic measures is of utmost priority.

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with a safe replicative niche, and so the bacteria are able to maintain a latent state for a prolonged time.

6835: 6821: 6602: 6431: 6373: 1641: 730: 318: 5802:"Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2" 1573:

Early case and twin studies have indicated that genetic components are important in host susceptibility to

6982: 6828: 6782: 6730: 6695: 6607: 6558: 6527: 6502: 6259: 5005:"Eighteenth-century genomes show that mixed infections were common at time of peak tuberculosis in Europe" 3472:

Supply P, Allix C, Lesjean S, Cardoso-Oelemann M, Rüsch-Gerdes S, Willery E, et al. (December 2006).

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Brynildsrud OB, Pepperell CS, Suffys P, Grandjean L, Monteserin J, Debech N, et al. (October 2018).

772: 7214: 7209: 6964: 6867: 6807: 6741: 6720: 6702: 6685: 5751:

Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, et al. (February 2012).

1175: 1146: 758: 523: 519: 511: 387: 181: 6094:"Early BCG vaccination is unrelated to pulmonary immunity against Mycobacterium tuberculosis in adults" 2564:

Flynn JL, Chan J (August 2003). "Immune evasion by Mycobacterium tuberculosis: living with the enemy".

1718: 6038: 4600:

Wirth T, Hildebrand F, Allix-Béguec C, Wölbeling F, Kubica T, Kremer K, et al. (September 2008).

4452:"Progenitor "Mycobacterium canettii" clone responsible for lymph node tuberculosis epidemic, Djibouti" 2466:

Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, et al. (January 1997).

1678:, tuberculosis may be caused by small living creatures transmitted through the air to other patients. 7158: 7052: 6628: 6592: 6570: 6422: 6389: 6362: 5917: 5655:"Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target" 5602: 5594: 5379:

Mousavi-Sagharchi SM, Afrazeh E, Seyyedian-Nikjeh SF, Meskini M, Doroud D, Siadat SD (21 June 2024).

5176: 5016: 4959: 4793: 4723: 4664: 4352: 4292: 4184: 3650: 3534: 3377: 2713: 2328: 1907: 779: 751: 6301: 6141: 4403:"Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans" 4010:"DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis" 2702:"Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis" 2700:

Schaaf K, Smith SR, Duverger A, Wagner F, Wolschendorf F, Westfall AO, et al. (February 2017).

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Research indicates there may be a correlation between BCG vaccination and better immune response to

1524:. Despite an additionally slow evolution rate, the emergence and spread of antibiotic resistance in 6863: 6758: 6661: 6641: 6548: 6470: 6382: 4841:"Stable association between strains of Mycobacterium tuberculosis and their human host populations" 815: 744: 440: 242: 6270: 4780:

Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, et al. (February 2006).

1088:, especially during the chronic phase of infection when other nutrients are likely not available. 6955: 6871: 6708: 6651: 6538: 6123: 5883: 5469: 4533: 3987: 3845: 3037: 2937: 2831: 2675: 2015: 1650: 1430:

lineages and/or social interactions that are shaped by shared cultural and geographic histories.

598:, respectively. The cell, outer membrane, periplasm, plasma membrane, and cytoplasm volumes were 535: 306: 203: 91: 4890:

Pepperell CS, Casto AM, Kitchen A, Granka JM, Cornejo OE, Holmes EC, et al. (August 2013).

3080:

Schaaf K, Hayley V, Speer A, Wolschendorf F, Niederweis M, Kutsch O, et al. (August 2016).

903:(trehalose dimycolate), which serves to increase survival within its host. Resistant strains of 7109: 5112:

Gutierrez MC, Brisse S, Brosch R, Fabre M, Omaïs B, Marmiesse M, et al. (September 2005).

4228:

Blow MJ, Clark TA, Daum CG, Deutschbauer AM, Fomenkov A, Fries R, et al. (February 2016).

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and tuberculosis disease indications were present in human bodies dating from 7000 BC found at

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originating from a person who has the disease either coughing, sneezing, speaking, or singing.

7166: 7039: 6563: 6487: 6220: 6115: 5994: 5945: 5875: 5831: 5782: 5733: 5684: 5632: 5558: 5523: 5461: 5420: 5402: 5361: 5298: 5288: 5243: 5204: 5145: 5094: 5042: 4985: 4948:"Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis" 4923: 4872: 4821: 4749: 4712:"Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis" 4692: 4633: 4582: 4525: 4481: 4432: 4380: 4318: 4261: 4210: 4156: 4090: 4041: 3979: 3943: 3894: 3837: 3796: 3747: 3668: 3593: 3503: 3454: 3405: 3364:

Mazars E, Lesjean S, Banuls AL, Gilbert M, Vincent V, Gicquel B, et al. (February 2001).

3346: 3301: 3209: 3160: 3111: 3060: 3029: 2988: 2929: 2900:"TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma" 2898:

Gern BH, Adams KN, Plumlee CR, Stoltzfus CR, Shehata L, Moguche AO, et al. (April 2021).

2880: 2823: 2788: 2739: 2667: 2632: 2581: 2546: 2497: 2422: 2356: 2292: 2243: 2182: 2172: 2102: 2053: 2043: 2007: 1966: 1925: 1876: 1824: 1787: 1761: 896: 842: 7181: 5800:

Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, et al. (September 2010).

4551:

Malm S, Linguissi LS, Tekwu EM, Vouvoungui JC, Kohl TA, Beckert P, et al. (March 2017).

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is part of a genetically related group of Mycobacterium species that has at least 9 members:

309:, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the 7171: 6885: 6353: 6210: 6105: 5984: 5976: 5935: 5925: 5865: 5821: 5813: 5772: 5764: 5723: 5715: 5674: 5666: 5622: 5612: 5550: 5513: 5503: 5451: 5410: 5392: 5351: 5341: 5235: 5194: 5184: 5135: 5125: 5084: 5076: 5032: 5024: 4975: 4967: 4913: 4903: 4862: 4852: 4811: 4801: 4739: 4731: 4682: 4672: 4623: 4613: 4572: 4564: 4515: 4471: 4463: 4422: 4414: 4370: 4360: 4308: 4300: 4251: 4241: 4200: 4192: 4146: 4136: 4080: 4072: 4031: 4021: 4008:

Shell SS, Prestwich EG, Baek SH, Shah RR, Sassetti CM, Dedon PC, et al. (4 July 2013).

3971: 3933: 3925: 3884: 3876: 3827: 3786: 3778: 3737: 3729: 3658: 3583: 3575: 3542: 3493: 3485: 3444: 3436: 3395: 3385: 3336: 3291: 3283: 3199: 3191: 3150: 3142: 3131:"Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways" 3101: 3093: 3019: 2978: 2968: 2919: 2911: 2870: 2862: 2849:

Marakalala MJ, Raju RM, Sharma K, Zhang YJ, Eugenin EA, Prideaux B, et al. (May 2016).

2815: 2778: 2770: 2729: 2721: 2659: 2622: 2612: 2573: 2536: 2528: 2487: 2479: 2412: 2404: 2346: 2336: 2282: 2274: 2233: 2225: 1997: 1956: 1915: 1866: 1858: 1816: 1751: 1478: 870: 854: 849:

has been shown to secrete and cover itself in 1-tuberculosinyladenosine (1-TbAd), a special

391: 364: 359: 302: 246: 148: 2599:

Buter J, Cheng TY, Ghanem M, Grootemaat AE, Raman S, Feng X, et al. (September 2019).

7135: 6896: 6666: 6446: 4401:

Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. (October 2013).

3082:"A Macrophage Infection Model to Predict Drug Efficacy Against Mycobacterium Tuberculosis" 3024: 3007: 2391:

van Ingen J, Rahim Z, Mulder A, Boeree MJ, Simeone R, Brosch R, et al. (April 2012).

1671: 1126:. In 2013, a study on the genome of several sensitive, ultraresistant, and multiresistant 350: 314: 250: 138: 4279:

Beaulaurier J, Zhang XS, Zhu S, Sebra R, Rosenbluh C, Deikus G, et al. (June 2015).

3639:"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence" 3637:

Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. (June 1998).

2957:"The role of the granuloma in expansion and dissemination of early tuberculous infection" 1896:"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence" 1894:

Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. (June 1998).

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complex members extracted from three 1,000-year-old Peruvian mummies, estimated that the

6249: 6070: 5921: 5598: 5415: 5380: 5282: 5180: 5065:"Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation" 5020: 4963: 4946:

Bos KI, Harkins KM, Herbig A, Coscolla M, Weber N, Comas I, et al. (October 2014).

4797: 4727: 4710:

Bos KI, Harkins KM, Herbig A, Coscolla M, Weber N, Comas I, et al. (October 2014).

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Please help update this article to reflect recent events or newly available information.

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Blouin Y, Cazajous G, Dehan C, Soler C, Vong R, Hassan MO, et al. (January 2014).

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Zhang Y, Mazurek GH, Cave MD, Eisenach KD, Pang Y, Murphy DT, et al. (June 1992).

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and how it has spread and co-evolved with humans through time. One study compared the

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Ramakrishnan L (April 2012). "Revisiting the role of the granuloma in tuberculosis".

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in mice. DnaE2 is an error-prone DNA repair polymerase that appears to contribute to

1325: 1321: 1304:(EAI), the Manila family of strains and some Manu (Indian) strains; lineage 2 is the 507: 415: 278: 270: 158: 128: 6127: 5473: 5003:

Kay GL, Sergeant MJ, Zhou Z, Chan JZ, Millard A, Quick J, et al. (April 2015).

3991: 3849: 3523:"Complications in the study of ancient tuberculosis: non-specificity of IS6110 PCRs" 3440: 3287: 2019: 7044: 6854: 6788: 6492: 6479: 5887: 5114:"Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis" 4892:"The role of selection in shaping diversity of natural M. tuberculosis populations" 4537: 3686: 3547: 3522: 2835: 1442: 1345: 1309: 892: 811: 800: 376: 368: 310: 286: 266: 254: 20: 6142:"Fact Sheets | Infection Control & Prevention | Fact Sheet – BCG Vaccine | TB" 2483: 265:

has an unusual, waxy coating on its cell surface primarily due to the presence of

5930: 5223: 5189: 5130: 4908: 4618: 4365: 4246: 4026: 3782: 3733: 2341: 2171:(4th ed.). Galveston (TX): University of Texas Medical Branch at Galveston. 1961: 1944: 818:, but they are unable to kill and digest the bacterium. Its cell wall is made of 7091: 7014: 6877: 6281: 6215: 6198: 3341: 3320: 2851:"Inflammatory signaling in human tuberculosis granulomas is spatially organized" 2393:"Characterization of Mycobacterium orygis as M. tuberculosis complex subspecies" 1687: 1657: 1512: 1462: 1333: 1297: 1229:(MTBC) has a number of members infecting various animal species, these include 1081: 900: 819: 506:

has a remarkably slow growth rate, doubling roughly once per day. Commonly used

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M. tuberculosis in the lungs, showing large cavities the bacteria have dissolved

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