'{{short description|Species of pathogenic bacteria that causes tuberculosis}} {{About|the bacterium|the infection|Tuberculosis}} {{Use dmy dates|date=March 2020}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Update|date=December 2022}}{{speciesbox | image = TB_Culture.jpg | image_caption = ''M. tuberculosis'' colonies | taxon = Mycobacterium tuberculosis | authority = Zopf 1883 | synonyms = Tubercle bacillus <small>[[Robert Koch|Koch]] 1882</small> }} [[File:Cavitary tuberculosis.jpg|thumb|M. tuberculosis in the lungs, showing large cavities the bacteria have dissolved]] '''''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]].<ref name="Gordon & Parish, 2018">{{cite journal | vauthors = Gordon SV, Parish T | title = Microbe Profile: Mycobacterium tuberculosis: Humanity's deadly microbial foe | journal = Microbiology | volume = 164 | issue = 4 | pages = 437–439 | date = April 2018 | pmid = 29465344 | doi = 10.1099/mic.0.000601 | doi-access = free }}</ref><ref name=Sherris>{{cite book| vauthors = Ryan KJ, Ray CG |title=Sherris Medical Microbiology : an Introduction to Infectious Diseases|date=2004|publisher=McGraw-Hill|location=New York|isbn=978-0-83-858529-0|page=439|edition=4th|chapter=Mycobacteria}}</ref> 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.<ref>{{cite journal | vauthors = Fu LM, Fu-Liu CS | title = Is Mycobacterium tuberculosis a closer relative to Gram-positive or Gram-negative bacterial pathogens? | journal = Tuberculosis | volume = 82 | issue = 2–3 | pages = 85–90 | date = 2002-01-01 | pmid = 12356459 | doi = 10.1054/tube.2002.0328 }}</ref> [[Acid-fastness|Acid-fast]] stains such as [[Ziehl–Neelsen stain|Ziehl–Neelsen]], or [[Fluorescence|fluorescent]] stains such as [[Auramine O|auramine]] are used instead to identify ''M. tuberculosis'' with a microscope. The physiology of ''M. tuberculosis'' is highly [[aerobic organism|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 [[Mantoux test|tuberculin skin test]], [[Acid-Fast Stain|acid-fast stain]], [[Microbiological culture|culture]], and [[polymerase chain reaction]].<ref name=Sherris/><ref name=":0">{{cite journal | vauthors = Cudahy P, Shenoi SV | title = Diagnostics for pulmonary tuberculosis | journal = Postgraduate Medical Journal | volume = 92 | issue = 1086 | pages = 187–193 | date = April 2016 | pmid = 27005271 | pmc = 4854647 | doi = 10.1136/postgradmedj-2015-133278 }}</ref> The ''M. tuberculosis'' [[genome]] was [[sequenced]] in 1998.<ref>{{cite journal | vauthors = Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG | title = Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence | journal = Nature | volume = 393 | issue = 6685 | pages = 537–44 | date = June 1998 | pmid = 9634230 | doi = 10.1038/31159 | bibcode = 1998Natur.393..537C | doi-access = free }}</ref><ref>{{cite journal | vauthors = Camus JC, Pryor MJ, Médigue C, Cole ST | title = Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv | journal = Microbiology | volume = 148 | issue = Pt 10 | pages = 2967–73 | date = October 2002 | pmid = 12368430 | doi = 10.1099/00221287-148-10-2967 | doi-access = free }}</ref> == Microbiology == ''M. tuberculosis'' [[obligate aerobe|requires oxygen to grow]], and is [[Motility|nonmotile]].<ref name="pmid10934532">{{cite journal | vauthors = Parish T, Stoker NG | title = Mycobacteria: bugs and bugbears (two steps forward and one step back) | journal = Molecular Biotechnology | volume = 13 | issue = 3 | pages = 191–200 | date = December 1999 | pmid = 10934532 | doi = 10.1385/MB:13:3:191 | s2cid = 28960959 | doi-access = free }}</ref><ref name=":1">{{Cite book |title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases | veditors = Bennett JE, Dolin R, Blaser MJ | vauthors = Fitzgerald DW, Sterline TR, Haas DW |date=2015|publisher=Elsevier Saunders |isbn=978-1-4557-4801-3 |pages=2787 |chapter=251 – Mycobacterium tuberculosis|oclc=903327877 }}</ref> It divides every 18–24 hours. This is extremely slow compared with other bacteria, which tend to have division times measured in minutes (''[[Escherichia coli]]'' can divide roughly every 20 minutes). It is a small [[bacillus (shape)|bacillus]] that can withstand weak [[disinfectant]]s and can survive in a dry state for weeks. Its unusual cell wall, rich in [[lipids]] such as [[mycolic acid]] and [[cord factor]] [[glycolipid]], is likely responsible for its resistance to [[Desiccation tolerance|desiccation]] and is a key [[virulence factor]].<ref>{{cite book|title=Medical Microbiology|vauthors=Murray PR, Rosenthal KS, Pfaller MA|publisher=Elsevier Mosby|year=2005}}</ref><ref name=":9">{{cite journal | vauthors = Hunter RL, Olsen MR, Jagannath C, Actor JK | title = Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease | journal = Annals of Clinical and Laboratory Science | volume = 36 | issue = 4 | pages = 371–386 | date = 2006 | pmid = 17127724 | url = https://pubmed.ncbi.nlm.nih.gov/17127724/ | access-date = 16 December 2022 | archive-date = 16 December 2022 | archive-url = https://web.archive.org/web/20221216103128/https://pubmed.ncbi.nlm.nih.gov/17127724/ | url-status = live }}</ref> === Microscopy === [[File:M.tuberculosis.jpg|thumb|Growth of Mycobacterium tuberculosis on Löwenstein-Jensen (A) and Ogawa medium (B), 6 weeks at 37°C. ]] Other bacteria are commonly identified with a microscope by staining them with [[Gram staining|Gram stain]]. However, the mycolic acid in the cell wall of ''M. tuberculosis'' does not absorb the stain. Instead, acid-fast stains such as [[Ziehl–Neelsen stain]], or fluorescent stains such as [[Auramine O|auramine]] are used.<ref name=":0" /> 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.<ref>{{Cite web |url= http://textbookofbacteriology.net/tuberculosis.html |title= Mycobacterium tuberculosis and Tuberculosis |vauthors= Todar K |website= textbookofbacteriology.net |access-date= 2016-12-24 |archive-date= 24 December 2016 |archive-url= https://web.archive.org/web/20161224162909/http://textbookofbacteriology.net/tuberculosis.html |url-status= live }}</ref> This appearance is referred to as cording, like strands of cord that make up a rope.<ref name=":1" /> ''M. tuberculosis'' is characterized in tissue by caseating [[granulomas]] containing [[Langhans giant cell]]s, which have a "horseshoe" pattern of nuclei.{{cn|date=May 2024}} === Culture === [[File:Slant tubes of Löwenstein-Jensen medium with control, M tuberculosis, M avium and M gordonae.jpg|thumb|upright=0.6|Slant tubes of Löwenstein-Jensen medium. From left to right:{{unordered list|item_style=margin-bottom: 0|Negative control|''M. tuberculosis'': Dry-appearing colonies|''[[Mycobacterium avium complex]]'': Wet-appearing colonies|''[[M. gordonae]]'': Yellowish colonies}}]] [[File:Mycobacteria Growth Indicator Tube (MGIT) samples in ultraviolet light.jpg|thumb|150px|[[Mycobacteria growth indicator tube]] samples emitting fluorescence in ultraviolet light]] ''M. tuberculosis'' can be grown in the laboratory. Compared to other commonly studied bacteria, ''M. tuberculosis'' has a remarkably slow growth rate, doubling roughly once per day. Commonly used [[Growth medium|media]] include liquids such as [[Middlebrook 7H9 Broth|Middlebrook 7H9]] or 7H12, egg-based solid media such as [[Löwenstein–Jensen medium|Lowenstein-Jensen]], and solid agar-based such as [[Middlebrook 7H11 Agar|Middlebrook 7H11]] or [[Middlebrook 7H10 Agar|7H10]].<ref name=":1" /> Visible colonies require several weeks to grow on agar plates. [[Mycobacteria growth indicator tube]]s can contain a gel that emits fluorescent light if mycobacteria are grown. It is distinguished from other mycobacteria by its production of [[catalase]] and [[Niacin (substance)|niacin]].<ref>{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK7812/|title=Medical Microbiology|vauthors=McMurray DN|date=1996|publisher=University of Texas Medical Branch at Galveston|isbn=978-0963117212|veditors=Baron S|edition=4th|location=Galveston (TX)|pmid=21413269|chapter=Mycobacteria and Nocardia|access-date=5 September 2017|archive-date=12 February 2009|archive-url=https://web.archive.org/web/20090212202626/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.1833|url-status=live}}</ref> Other tests to confirm its identity include [[gene probe]]s and [[MALDI-TOF]].<ref>{{cite journal | vauthors = Bicmen C, Gunduz AT, Coskun M, Senol G, Cirak AK, Ozsoz A | title = 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 | journal = Journal of Clinical Microbiology | volume = 49 | issue = 8 | pages = 2874–78 | date = August 2011 | pmid = 21653780 | pmc = 3147717 | doi = 10.1128/JCM.00612-11 }}</ref><ref>{{cite journal | vauthors = Saleeb PG, Drake SK, Murray PR, Zelazny AM | title = Identification of mycobacteria in solid-culture media by matrix-assisted laser desorption ionization-time of flight mass spectrometry | journal = Journal of Clinical Microbiology | volume = 49 | issue = 5 | pages = 1790–94 | date = May 2011 | pmid = 21411597 | pmc = 3122647 | doi = 10.1128/JCM.02135-10 }}</ref> === Morphology === Analysis of ''Mycobacterium tuberculosis'' via [[scanning electron microscope]] shows the bacteria are {{val|2.71|1.05|u=um}} in length with an average diameter of {{val|0.0345|0.029|u=um}}.<ref name=":10" /> The [[Bacterial cell structure|outer membrane]] and plasma membrane surface areas were measured to be {{val|3.04|1.33|u=um2}} and {{val|2.67|1.19|u=um2}}, respectively. The cell, outer membrane, periplasm, plasma membrane, and cytoplasm volumes were {{val|0.293|0.113|u=fl}} (= μm³), {{val|0.006|0.003|u=fl}}, {{val|0.060|0.021|u=fl}}, {{val|0.019|0.008|u=fl}}, and {{val|0.210|0.091|u=fl}}, respectively. The average total [[Ribosome recycling factor|ribosome]] number was {{val|1672|568}} with ribosome density about {{val|716.5|171.4|up=0.1 fl}}.<ref name=":10" /> {| class="wikitable floatcenter" |+''M. tb'' morphology summary<ref name=":10">{{cite journal | vauthors = Yamada H, Yamaguchi M, Chikamatsu K, Aono A, Mitarai S | title = Structome analysis of virulent Mycobacterium tuberculosis, which survives with only 700 ribosomes per 0.1 fl of cytoplasm | journal = PLOS ONE | volume = 10 | issue = 1 | pages = e0117109 | date = 2015-01-28 | pmid = 25629354 | pmc = 4309607 | doi = 10.1371/journal.pone.0117109 | bibcode = 2015PLoSO..1017109Y | doi-access = free }}</ref> !Feature !Magnitude |- |Length |2.71 ± 1.05μm |- |Outer membrane surface area |3.04 ± 1.33 μm² |- |Cell volume |0.293 ± 0.113 fl (= μm³) |} === Related Mycobacterium species === {{See also|Mycobacterium tuberculosis complex}} ''M. tuberculosis'' is part of a genetically related group of Mycobacterium species that has at least 9 members: * ''M. tuberculosis''<ref name="van Ingen2012">{{cite journal |vauthors=van Ingen J, Rahim Z, Mulder A, Boeree MJ, Simeone R, Brosch R, van Soolingen D |date=April 2012 |title=Characterization of Mycobacterium orygis as M. tuberculosis complex subspecies |journal=Emerging Infectious Diseases |volume=18 |issue=4 |pages=653–55 |doi=10.3201/eid1804.110888 |pmc=3309669 |pmid=22469053}}</ref> ''sensu stricto'' * ''[[Mycobacterium africanum|M. africanum]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium canettii|M. canettii]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium bovis|M. bovis]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium caprae|M. caprae]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium microti|M. microti]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium pinnipedii|M. pinnipedii]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium mungi|M. mungi]]''<ref name="van Ingen2012" /> * ''[[Mycobacterium orygis|M. orygis]]''<ref name="van Ingen2012" /> ==Pathophysiology== Humans are the only known reservoirs of ''M. tuberculosis''. A misconception is that ''M. tuberculosis'' can be spread by shaking hands, making contact with toilet seats, sharing food or drink, or sharing toothbrushes. However, major spread is through [[air droplets]] originating from a person who has the disease either coughing, sneezing, speaking, or singing.<ref>{{cite web | publisher = Center for Disease Control | title = How TB Spreads | date = 26 July 2016 | url = https://www.cdc.gov/tb/topic/basics/howtbspreads.htm | access-date = 14 March 2018 | archive-date = 30 July 2022 | archive-url = https://web.archive.org/web/20220730084503/https://www.cdc.gov/tb/topic/basics/howtbspreads.htm | url-status = live }}</ref> When in the lungs, ''M. tuberculosis'' is [[Phagocytosis|phagocytosed]] by [[alveolar macrophage]]s, but they are unable to kill and digest the bacterium. Its cell wall is made of [[cord factor]] glycolipids that inhibit the fusion of the [[phagosome]] with the [[lysosome]], which contains a host of antibacterial factors.<ref name="pmid8975927">{{cite journal | vauthors = Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, Kornfeld H | title = Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis | journal = Infection and Immunity | volume = 65 | issue = 1 | pages = 298–304 | date = January 1997 | doi = 10.1128/IAI.65.1.298-304.1997 | pmid = 8975927 | pmc = 174591 }}</ref><ref name=":9" /> Specifically, ''M. tuberculosis'' blocks the bridging molecule, early endosomal autoantigen 1 ([[EEA1]]); however, this blockade does not prevent fusion of vesicles filled with nutrients. In addition, production of the diterpene [[isotuberculosinol]] prevents maturation of the phagosome.<ref>{{cite journal | vauthors = Mann FM, Xu M, Chen X, Fulton DB, Russell DG, Peters RJ | title = Edaxadiene: a new bioactive diterpene from Mycobacterium tuberculosis | journal = Journal of the American Chemical Society | volume = 131 | issue = 48 | pages = 17526–27 | date = December 2009 | pmid = 19583202 | pmc = 2787244 | doi = 10.1021/ja9019287 }}</ref> The bacteria also evades macrophage-killing by neutralizing reactive nitrogen intermediates.<ref>{{cite journal | vauthors = Flynn JL, Chan J | title = Immune evasion by Mycobacterium tuberculosis: living with the enemy | journal = Current Opinion in Immunology | volume = 15 | issue = 4 | pages = 450–55 | date = August 2003 | pmid = 12900278 | doi = 10.1016/S0952-7915(03)00075-X }}</ref> More recently, ''M. tuberculosis'' has been shown to secrete and cover itself in 1-tuberculosinyladenosine (1-TbAd), a special [[nucleoside]] that acts as an [[Base (chemistry)|antacid]], allowing it to neutralize pH and induce swelling in lysosomes.<ref>{{cite journal | vauthors = Buter J, Cheng TY, Ghanem M, Grootemaat AE, Raman S, Feng X, Plantijn AR, Ennis T, Wang J, Cotton RN, Layre E, Ramnarine AK, Mayfield JA, Young DC, Jezek Martinot A, Siddiqi N, Wakabayashi S, Botella H, Calderon R, Murray M, Ehrt S, Snider BB, Reed MB, Oldfield E, Tan S, Rubin EJ, Behr MA, van der Wel NN, Minnaard AJ, Moody DB | title = Mycobacterium tuberculosis releases an antacid that remodels phagosomes | journal = Nature Chemical Biology | volume = 15 | issue = 9 | pages = 889–899 | date = September 2019 | pmid = 31427817 | pmc = 6896213 | doi = 10.1038/s41589-019-0336-0 | doi-access = free }}</ref><ref name=":4">{{cite journal | vauthors = Brodin P, Hoffmann E | title = T(oo)bAd | journal = Nature Chemical Biology | volume = 15 | issue = 9 | pages = 849–850 | date = September 2019 | pmid = 31427816 | doi = 10.1038/s41589-019-0347-x | s2cid = 209569609 }}</ref> In ''M. tuberculosis'' infections, [[PPM1A]] 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 pathways.<ref name="Schaaf_2017">{{cite journal | vauthors = Schaaf K, Smith SR, Duverger A, Wagner F, Wolschendorf F, Westfall AO, Kutsch O, Sun J | title = Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis | journal = Scientific Reports | volume = 7 | issue = | pages = 42101 | date = February 2017 | pmid = 28176854 | pmc = 5296758 | doi = 10.1038/srep42101 | bibcode = 2017NatSR...742101S }}</ref> With kinome analysis, the [[JNK/AP-1 pathway|JNK/AP-1 signalling pathway]] 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.<ref name="Schaaf_2017"/> As a result of having apoptosis being suppressed, it provides ''M. tuberculosis'' with a safe replicative niche, and so the bacteria are able to maintain a latent state for a prolonged time.<ref name="pmid23841514">{{cite journal | vauthors = Aberdein JD, Cole J, Bewley MA, Marriott HM, Dockrell DH | title = Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing | journal = Clinical and Experimental Immunology | volume = 174 | issue = 2 | pages = 193–202 | date = November 2013 | pmid = 23841514 | pmc = 3828822 | doi = 10.1111/cei.12170 }}</ref> [[Granuloma]]s, 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.<ref>{{cite journal | vauthors = Ramakrishnan L | title = Revisiting the role of the granuloma in tuberculosis | journal = Nature Reviews. Immunology | volume = 12 | issue = 5 | pages = 352–366 | date = April 2012 | pmid = 22517424 | doi = 10.1038/nri3211 | s2cid = 1139969 }}</ref><ref>{{cite journal | vauthors = Marakalala MJ, Raju RM, Sharma K, Zhang YJ, Eugenin EA, Prideaux B, Daudelin IB, Chen PY, Booty MG, Kim JH, Eum SY, Via LE, Behar SM, Barry CE, Mann M, Dartois V, Rubin EJ | title = Inflammatory signaling in human tuberculosis granulomas is spatially organized | journal = Nature Medicine | volume = 22 | issue = 5 | pages = 531–538 | date = May 2016 | pmid = 27043495 | pmc = 4860068 | doi = 10.1038/nm.4073 }}</ref><ref>{{cite journal | vauthors = Gern BH, Adams KN, Plumlee CR, Stoltzfus CR, Shehata L, Moguche AO, Busman-Sahay K, Hansen SG, Axthelm MK, Picker LJ, Estes JD, Urdahl KB, Gerner MY | title = TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma | journal = Cell Host & Microbe | volume = 29 | issue = 4 | pages = 594–606.e6 | date = April 2021 | pmid = 33711270 | pmc = 8624870 | doi = 10.1016/j.chom.2021.02.005 | s2cid = 232217715 }}</ref><ref>{{cite journal | vauthors = Davis JM, Ramakrishnan L | title = The role of the granuloma in expansion and dissemination of early tuberculous infection | journal = Cell | volume = 136 | issue = 1 | pages = 37–49 | date = January 2009 | pmid = 19135887 | pmc = 3134310 | doi = 10.1016/j.cell.2008.11.014 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cohen SB, Gern BH, Urdahl KB | title = The Tuberculous Granuloma and Preexisting Immunity | journal = Annual Review of Immunology | volume = 40 | issue = 1 | pages = 589–614 | date = April 2022 | pmid = 35130029 | doi = 10.1146/annurev-immunol-093019-125148 | s2cid = 246651980 | doi-access = free }}</ref> The ability to construct ''M. tuberculosis'' mutants and test individual gene products for specific functions has significantly advanced the understanding of its [[pathogenesis]] and [[virulence factors]]. Many secreted and exported proteins are known to be important in pathogenesis.<ref name= WooldridgeK>{{cite book |editor= Wooldridge K | year=2009 |title=Bacterial Secreted Proteins: Secretory Mechanisms and Role in Pathogenesis | publisher=Caister Academic Press | isbn= 978-1-904455-42-4}}</ref> For example, one such virulence factor is [[cord factor]] (trehalose dimycolate), which serves to increase survival within its host. Resistant strains of ''M. tuberculosis'' 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 [[Intracellular parasite|intracellular]] ''M. tuberculosis'' due to their inability to effectively penetrate the macrophage niche.<ref name="Schaaf_2016">{{cite journal | vauthors = Schaaf K, Hayley V, Speer A, Wolschendorf F, Niederweis M, Kutsch O, Sun J | title = A Macrophage Infection Model to Predict Drug Efficacy Against Mycobacterium Tuberculosis | journal = Assay and Drug Development Technologies | volume = 14 | issue = 6 | pages = 345–354 | date = August 2016 | pmid = 27327048 | pmc = 4991579 | doi = 10.1089/adt.2016.717 }}</ref> 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,<ref name="Takekawa_19989">{{cite journal | vauthors = Takekawa M, Maeda T, Saito H | title = Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways | journal = The EMBO Journal | volume = 17 | issue = 16 | pages = 4744–52 | date = August 1998 | pmid = 9707433 | pmc = 1170803 | doi = 10.1093/emboj/17.16.4744 }}</ref> hence the phosphorylation of JNK would cause apoptosis to occur.<ref name="Dhanasekaran_2008">{{cite journal | vauthors = Dhanasekaran DN, Reddy EP | title = JNK signaling in apoptosis | journal = Oncogene | volume = 27 | issue = 48 | pages = 6245–51 | date = October 2008 | pmid = 18931691 | pmc = 3063296 | doi = 10.1038/onc.2008.301 | url = }}</ref> Since PPM1A levels are elevated during ''M. tuberculosis'' infections, by inhibiting the PPM1A signalling pathways, it could potentially be a therapeutic method to kill ''M. tuberculosis''-infected macrophages by restoring its normal apoptotic function in defence of pathogens.<ref name="Schaaf_2017"/> By targeting the PPM1A-JNK signalling axis pathway, then, it could eliminate ''M. tuberculosis''-infected macrophages.<ref name="Schaaf_2017"/> The ability to restore macrophage apoptosis to ''M. tuberculosis''-infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche.<ref>The ability to restore macrophage apoptosis to ''M. tuberculosis'' infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche (M),</ref> thus decreasing the treatment times for ''M. tuberculosis'' infections. Symptoms of ''M. tuberculosis'' include coughing that lasts for more than three weeks, [[hemoptysis]], chest pain when breathing or coughing, weight loss, fatigue, fever, night sweats, chills, and loss of appetite. ''M. tuberculosis'' 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.<ref>{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/syc-20351250|title=Tuberculosis – Symptoms and causes|website=Mayo Clinic|language=en|access-date=2019-11-12|archive-date=20 October 2008|archive-url=https://web.archive.org/web/20081020192205/http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|url-status=live}}</ref> ===Strain variation=== 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 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.{{cn|date=May 2024}} Until the early 2000s, ''M. tuberculosis'' strains were typed by [[pulsed field gel electrophoresis]].<ref>{{cite journal | vauthors = Zhang Y, Mazurek GH, Cave MD, Eisenach KD, Pang Y, Murphy DT, Wallace RJ | title = DNA polymorphisms in strains of Mycobacterium tuberculosis analyzed by pulsed-field gel electrophoresis: a tool for epidemiology | journal = Journal of Clinical Microbiology | volume = 30 | issue = 6 | pages = 1551–56 | date = June 1992 | doi = 10.1128/JCM.30.6.1551-1556.1992 | pmid = 1352518 | pmc = 265327 | url = }}</ref> This has now been superseded by [[variable number tandem repeat|variable numbers of tandem repeats]] (VNTR), which is technically easier to perform and allows better discrimination between strains. This method makes use of the presence of repeated [[DNA]] sequences within the ''M. tuberculosis'' genome.{{cn|date=May 2024}} Three generations of VNTR typing for ''M. tuberculosis'' are noted. The first scheme, called exact tandem repeat, used only five loci,<ref>{{cite journal | vauthors = Frothingham R, Meeker-O'Connell WA | title = Genetic diversity in the ''Mycobacterium tuberculosis'' complex based on variable numbers of tandem DNA repeats | journal = Microbiology | volume = 144 | issue = Pt 5 | pages = 1189–96 | date = May 1998 | pmid = 9611793 | doi = 10.1099/00221287-144-5-1189 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Mazars E, Lesjean S, Banuls AL, Gilbert M, Vincent V, Gicquel B, Tibayrenc M, Locht C, Supply P | title = High-resolution minisatellite-based typing as a portable approach to global analysis of Mycobacterium tuberculosis molecular epidemiology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 1901–06 | date = February 2001 | pmid = 11172048 | pmc = 29354 | doi = 10.1073/pnas.98.4.1901 | bibcode = 2001PNAS...98.1901M | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hawkey PM, Smith EG, Evans JT, Monk P, Bryan G, Mohamed HH, Bardhan M, Pugh RN | title = 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 | journal = Journal of Clinical Microbiology | volume = 41 | issue = 8 | pages = 3514–20 | date = August 2003 | pmid = 12904348 | pmc = 179797 | doi = 10.1128/JCM.41.8.3514-3520.2003 }}</ref> The third generation (mycobacterial 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 ''M. tuberculosis''.<ref>{{cite journal | vauthors = Supply P, Allix C, Lesjean S, Cardoso-Oelemann M, Rüsch-Gerdes S, Willery E, Savine E, de Haas P, van Deutekom H, Roring S, Bifani P, Kurepina N, Kreiswirth B, Sola C, Rastogi N, Vatin V, Gutierrez MC, Fauville M, Niemann S, Skuce R, Kremer K, Locht C, van Soolingen D | title = Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis | journal = Journal of Clinical Microbiology | volume = 44 | issue = 12 | pages = 4498–510 | date = December 2006 | pmid = 17005759 | pmc = 1698431 | doi = 10.1128/JCM.01392-06 }}</ref> However, with regard to archaeological remains, additional evidence may be required because of possible contamination from related soil bacteria.<ref>{{Cite journal| vauthors = Müller R, Roberts CA, Brown TA |year=2015|title=Complications in the study of ancient tuberculosis: non-specificity of IS6110 PCRs|journal=Science and Technology of Archaeological Research|volume=1|issue=1|doi=10.1179/2054892314Y.0000000002|pages=1–8|bibcode=2015STAR....1....1M |doi-access=free}}</ref> Antibiotic resistance in ''M. tuberculosis'' typically occurs due to either the accumulation of mutations in the genes targeted by the antibiotic or a change in titration of the drug.<ref>{{cite journal | vauthors = Rattan A, Kalia A, Ahmad N | title = Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives | journal = Emerging Infectious Diseases | volume = 4 | issue = 2 | pages = 195–209 | date = June 1998 | pmid = 9621190 | pmc = 2640153 | doi = 10.3201/eid0402.980207 }}</ref> ''M. tuberculosis'' 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 ''M. tuberculosis'' (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).<ref>{{cite web | publisher = Center for Disease Control | title = Drug-resistant TB | date = April 2014 | url = https://www.cdc.gov/tb/topic/drtb/ | access-date = 10 September 2017 | archive-date = 6 October 2022 | archive-url = https://web.archive.org/web/20221006054241/https://www.cdc.gov/TB/Topic/DRTB/ | url-status = live }}</ref> [[File:Mycobacterium tuberculosis Ziehl-Neelsen stain 640.jpg|thumb|right|''M. tuberculosis'' (stained red) in tissue (blue)]] [[File:Chording mycobacterium tuberculesis culture.jpg|thumb|Cording ''M. tuberculosis'' (H37Rv strain) culture on the luminescent microscopy]] ==Genome== The genome of the [[H37Rv]] strain was published in 1998.<ref>{{cite journal | vauthors = Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG | title = Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence | journal = Nature | volume = 393 | issue = 6685 | pages = 537–44 | date = June 1998 | pmid = 9634230 | doi = 10.1038/31159 | bibcode = 1998Natur.393..537C | doi-access = free }}</ref><ref>{{cite web |url=http://www.sanger.ac.uk/Projects/M_tuberculosis/ |title=''Mycobacterium tuberculosis'' |publisher=Sanger Institute |date=2007-03-29 |access-date=2008-11-16 |archive-date=9 November 2008 |archive-url=https://web.archive.org/web/20081109114150/http://www.sanger.ac.uk/Projects/M_tuberculosis/ |url-status=live }}</ref> 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 [[pseudogene]]s.{{cn|date=May 2024}} '''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.<ref>{{cite journal | vauthors = Bloch H, Segal W | title = Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro | journal = Journal of Bacteriology | volume = 72 | issue = 2 | pages = 132–41 | date = August 1956 | doi = 10.1128/JB.72.2.132-141.1956 | pmid = 13366889 | pmc = 357869 | url = }}</ref> ''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.<ref>{{cite journal | vauthors = Wipperman MF, Sampson NS, Thomas ST | title = Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 49 | issue = 4 | pages = 269–93 | date = 2014 | pmid = 24611808 | pmc = 4255906 | doi = 10.3109/10409238.2014.895700 }}</ref> '''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.<ref>{{cite journal | vauthors = Glickman MS, Jacobs WR | title = Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline | journal = Cell | volume = 104 | issue = 4 | pages = 477–85 | date = February 2001 | pmid = 11239406 | doi = 10.1016/S0092-8674(01)00236-7 | s2cid = 11557497 | doi-access = free }}</ref> '''Noncoding RNAs'''. [[Mycobacterium tuberculosis sRNA|Nine noncoding sRNAs]] have been characterised in ''M. tuberculosis'',<ref>{{cite journal | vauthors = Arnvig KB, Young DB | title = Identification of small RNAs in Mycobacterium tuberculosis | journal = Molecular Microbiology | volume = 73 | issue = 3 | pages = 397–408 | date = August 2009 | pmid = 19555452 | pmc = 2764107 | doi = 10.1111/j.1365-2958.2009.06777.x }}</ref> with a further 56 predicted in a [[bioinformatics]] screen.<ref>{{cite journal | vauthors = Livny J, Brencic A, Lory S, Waldor MK | title = Identification of 17 Pseudomonas aeruginosa sRNAs and prediction of sRNA-encoding genes in 10 diverse pathogens using the bioinformatic tool sRNAPredict2 | journal = Nucleic Acids Research | volume = 34 | issue = 12 | pages = 3484–93 | year = 2006 | pmid = 16870723 | pmc = 1524904 | doi = 10.1093/nar/gkl453 }}</ref> '''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''.<ref>{{cite journal | vauthors = Zhang H, Li D, Zhao L, Fleming J, Lin N, Wang T, Liu Z, Li C, Galwey N, Deng J, Zhou Y, Zhu Y, Gao Y, Wang T, Wang S, Huang Y, Wang M, Zhong Q, Zhou L, Chen T, Zhou J, Yang R, Zhu G, Hang H, Zhang J, Li F, Wan K, Wang J, Zhang XE, Bi L | title = Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance | journal = Nature Genetics | volume = 45 | issue = 10 | pages = 1255–60 | date = October 2013 | pmid = 23995137 | doi = 10.1038/ng.2735 | s2cid = 14396673 }}</ref> '''Epigenome'''. [[Single-molecule real-time sequencing]] and subsequent bioinformatic analysis has identified three [[DNA methyltransferase|DNA methyltransferases]] in ''M. tuberculosis,'' <u>'''M'''</u>ycobacterial '''<u>A</u>'''denine '''<u>M</u>'''ethyltransferases A (MamA),<ref name=":11">{{cite journal | vauthors = Shell SS, Prestwich EG, Baek SH, Shah RR, Sassetti CM, Dedon PC, Fortune SM | title = DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis | journal = PLOS Pathogens | volume = 9 | issue = 7 | pages = e1003419 | date = 2013-07-04 | pmid = 23853579 | pmc = 3701705 | doi = 10.1371/journal.ppat.1003419 | doi-access = free }}</ref> B (MamB),<ref>{{cite journal | vauthors = Zhu L, Zhong J, Jia X, Liu G, Kang Y, Dong M, Zhang X, Li Q, Yue L, Li C, Fu J, Xiao J, Yan J, Zhang B, Lei M, Chen S, Lv L, Zhu B, Huang H, Chen F | title = Precision methylome characterization of Mycobacterium tuberculosis complex (MTBC) using PacBio single-molecule real-time (SMRT) technology | journal = Nucleic Acids Research | volume = 44 | issue = 2 | pages = 730–743 | date = January 2016 | pmid = 26704977 | pmc = 4737169 | doi = 10.1093/nar/gkv1498 }}</ref> and C (MamC'').<ref name=":12">{{cite journal | vauthors = Modlin SJ, Conkle-Gutierrez D, Kim C, Mitchell SN, Morrissey C, Weinrick BC, Jacobs WR, Ramirez-Busby SM, Hoffner SE, Valafar F | title = Drivers and sites of diversity in the DNA adenine methylomes of 93 <i>Mycobacterium tuberculosis</i> complex clinical isolates | journal = eLife | volume = 9 | pages = e58542 | date = October 2020 | pmid = 33107429 | doi = 10.7554/eLife.58542 | doi-access = free | veditors = Stallings CL, Soldati-Favre D, Casadesús J | pmc = 7591249 }}</ref> ''All three are [[DNA adenine methylase|adenine methyltransferases]], and each are functional in some clinical strains of ''M. tuberculosis''and not in others.''<ref>{{cite journal | vauthors = Phelan J, de Sessions PF, Tientcheu L, Perdigao J, Machado D, Hasan R, Hasan Z, Bergval IL, Anthony R, McNerney R, Antonio M, Portugal I, Viveiros M, Campino S, Hibberd ML, Clark TG | title = Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 160 | date = January 2018 | pmid = 29317751 | doi = 10.1038/s41598-017-18188-y | bibcode = 2018NatSR...8..160P | hdl = 10362/116703 | hdl-access = free }}</ref><ref name=":12" /> ''Unlike DNA methyltransferases in most bacteria, which invariably methylate the [[Adenine|adenines]] at their targeted sequence,<ref>{{cite journal | vauthors = Blow MJ, Clark TA, Daum CG, Deutschbauer AM, Fomenkov A, Fries R, Froula J, Kang DD, Malmstrom RR, Morgan RD, Posfai J, Singh K, Visel A, Wetmore K, Zhao Z, Rubin EM, Korlach J, Pennacchio LA, Roberts RJ | title = The Epigenomic Landscape of Prokaryotes | journal = PLOS Genetics | volume = 12 | issue = 2 | pages = e1005854 | date = February 2016 | pmid = 26870957 | pmc = 4752239 | doi = 10.1371/journal.pgen.1005854 | doi-access = free }}</ref> some strains of ''M. tuberculosis'' carry mutations in MamA that cause partial methylation of targeted adenine bases.<ref name=":12" /> This occurs as intracellular stochastic methylation, where a some targeted adenine bases on a given DNA molecule are methylated while others remain unmethylated.<ref name=":12" /><ref>{{cite journal | vauthors = Beaulaurier J, Zhang XS, Zhu S, Sebra R, Rosenbluh C, Deikus G, Shen N, Munera D, Waldor MK, Chess A, Blaser MJ, Schadt EE, Fang G | title = Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes | journal = Nature Communications | volume = 6 | issue = 1 | pages = 7438 | date = June 2015 | pmid = 26074426 | pmc = 4490391 | doi = 10.1038/ncomms8438 | bibcode = 2015NatCo...6.7438B }}</ref> MamA mutations causing intercellular mosaic methylation are most common in the globally successful Beijing sublineage of ''M. tuberculosis.<ref name=":12" />'' Due to the influence of methylation on gene expression at some locations in the genome,<ref name=":11" /> it has been hypothesized that IMM may give rise to phenotypic diversity, and partially responsible for the global success of Beijing sublineage.<ref name=":12" /> ==Evolution== The [[Mycobacterium tuberculosis complex|''M. tuberculosis'' complex]] evolved in Africa and most probably in the [[Horn of Africa]].<ref name=Blouin2012>{{cite journal | vauthors = Blouin Y, Hauck Y, Soler C, Fabre M, Vong R, Dehan C, Cazajous G, Massoure PL, Kraemer P, Jenkins A, Garnotel E, Pourcel C, Vergnaud G | title = Significance of the identification in the Horn of Africa of an exceptionally deep branching Mycobacterium tuberculosis clade | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e52841 | year = 2012 | pmid = 23300794 | pmc = 3531362 | doi = 10.1371/journal.pone.0052841 | bibcode = 2012PLoSO...752841B | doi-access = free }}</ref><ref name="Comes et. al.">{{cite journal | vauthors = Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao Q, Young D, Gagneux S | title = Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans | journal = Nature Genetics | volume = 45 | issue = 10 | pages = 1176–82 | date = October 2013 | pmid = 23995134 | pmc = 3800747 | doi = 10.1038/ng.2744 }}</ref> In addition to ''M. tuberculosis'', the [[Mycobacterium tuberculosis complex|''M. tuberculosis'' complex]] (MTBC) has a number of members infecting various animal species, these include ''M. africanum'', ''M. bovis'' (Dassie's bacillus), ''M. caprae'', ''M. microti'', ''M. mungi, M. orygis'', and ''M. pinnipedii''. This group may also include the ''M. canettii'' clade. These animal strains of MTBC do not strictly deserve species status, as they are all closely related and embedded in the ''M. tuberculosis'' phylogeny, but for historic reasons, they currently hold species status.{{cn|date=May 2024}} The ''M. canettii'' clade – which includes ''M. prototuberculosis'' – is a group of smooth-colony ''Mycobacterium'' species. Unlike the established members of the ''M. tuberculosis'' 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 ''M. tuberculosis'' appears to be ''M. canettii'', first described in 1969.<ref name=Blouin2014>{{cite journal | vauthors = Blouin Y, Cazajous G, Dehan C, Soler C, Vong R, Hassan MO, Hauck Y, Boulais C, Andriamanantena D, Martinaud C, Martin É, Pourcel C, Vergnaud G | title = Progenitor "Mycobacterium canettii" clone responsible for lymph node tuberculosis epidemic, Djibouti | journal = Emerging Infectious Diseases | volume = 20 | issue = 1 | pages = 21–28 | date = January 2014 | pmid = 24520560 | pmc = 3884719 | doi = 10.3201/eid2001.130652 }}</ref> The established members of the ''M. tuberculosis'' 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 [[East Africa]]n-[[India]]n (EAI), the Manila family of strains and some Manu (Indian) strains; lineage 2 is the [[Beijing]] group; lineage 3 includes the [[Central Asia]]n (CAS) strains; lineage 4 includes the [[Ghana]] and [[Haarlem]] (H/T), [[Latin America]]-[[Mediterranean]] (LAM) and X strains; types 5 and 6 correspond to ''M. africanum'' and are observed predominantly and at high frequencies in [[West Africa]]. A seventh type has been isolated from the Horn of Africa.<ref name="Blouin2012" /> The other species of this complex belong to a number of spoligotypes and do not normally infect humans.{{cn|date=May 2024}} Lineages 2, 3 and 4 all share a unique deletion event (tbD1) and thus form a monophyletic group.<ref name="Galagan 307–320">{{cite journal | vauthors = Galagan JE | title = Genomic insights into tuberculosis | journal = Nature Reviews. Genetics | volume = 15 | issue = 5 | pages = 307–20 | date = May 2014 | pmid = 24662221 | doi = 10.1038/nrg3664 | s2cid = 7371757 | doi-access = free }}</ref> 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 [[Tanzania]]) and CAS-Delhi (found in India and [[Saudi Arabia]]).{{cn|date=May 2024}} 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.<ref name=Malm2017>{{cite journal | vauthors = Malm S, Linguissi LS, Tekwu EM, Vouvoungui JC, Kohl TA, Beckert P, Sidibe A, Rüsch-Gerdes S, Madzou-Laboum IK, Kwedi S, Penlap Beng V, Frank M, Ntoumi F, Niemann S | title = New Mycobacterium tuberculosis Complex Sublineage, Brazzaville, Congo | journal = Emerging Infectious Diseases | volume = 23 | issue = 3 | pages = 423–29 | date = March 2017 | pmid = 28221129 | pmc = 5382753 | doi = 10.3201/eid2303.160679 }}</ref> A much cited study reported that ''M. tuberculosis'' has co-evolved with human populations, and that the [[most recent common ancestor]] of the ''M. tuberculosis'' complex evolved between 40,000 and 70,000 years ago.<ref name=Wirth2008>{{cite journal | vauthors = Wirth T, Hildebrand F, Allix-Béguec C, Wölbeling F, Kubica T, Kremer K, van Soolingen D, Rüsch-Gerdes S, Locht C, Brisse S, Meyer A, Supply P, Niemann S | title = Origin, spread and demography of the Mycobacterium tuberculosis complex | journal = PLOS Pathogens | volume = 4 | issue = 9 | pages = e1000160 | date = September 2008 | pmid = 18802459 | pmc = 2528947 | doi = 10.1371/journal.ppat.1000160 | doi-access = free }}</ref><ref name="Galagan 307–320"/> However, a later study that included genome sequences from ''M. tuberculosis'' complex members extracted from three 1,000-year-old Peruvian mummies, came to quite different conclusions. If the [[most recent common ancestor]] of the ''M. tuberculosis'' 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 ''M. tuberculosis'' complex as little as 6000 years ago.<ref name="Eldholm et al">{{cite journal | vauthors = Eldholm V, Pettersson JH, Brynildsrud OB, Kitchen A, Rasmussen EM, Lillebaek T, Rønning JO, Crudu V, Mengshoel AT, Debech N, Alfsnes K, Bohlin J, Pepperell CS, Balloux F | title = Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 48 | pages = 13881–86 | date = November 2016 | pmid = 27872285 | pmc = 5137683 | doi = 10.1073/pnas.1611283113 | bibcode = 2016PNAS..11313881E | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bos KI, Harkins KM, Herbig A, Coscolla M, Weber N, Comas I, Forrest SA, Bryant JM, Harris SR, Schuenemann VJ, Campbell TJ, Majander K, Wilbur AK, Guichon RA, Wolfe Steadman DL, Cook DC, Niemann S, Behr MA, Zumarraga M, Bastida R, Huson D, Nieselt K, Young D, Parkhill J, Buikstra JE, Gagneux S, Stone AC, Krause J | title = Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis | journal = Nature | volume = 514 | issue = 7523 | pages = 494–497 | date = October 2014 | pmid = 25141181 | pmc = 4550673 | doi = 10.1038/nature13591 | bibcode = 2014Natur.514..494B }}</ref> An analysis of over 3000 strains of ''M. bovis'' from 35 countries suggested an Africa origin for this species.<ref name=Loiseau2020>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 ''Mycobacterium bovis''. Evol Med Public Health. 2020 Jan 31;2020(1):49–59</ref> ===Co-evolution with modern humans=== There are currently two narratives existing in parallel regarding the age of [[Mycobacterium tuberculosis complex|MTBC]] and how it has spread and co-evolved with humans through time. One study compared the ''M. tuberculosis'' phylogeny to a human mitochondrial genome phylogeny and interpreted these as being highly similar. Based on this, the study suggested that ''M. tuberculosis'', 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.<ref name="Comes et. al." /> Applying this time scale, the study found that the ''M. tuberculosis'' [[effective population size]] expanded during the [[Neolithic Demographic Transition]] (around 10,000 years ago) and suggested that ''M. tuberculosis'' 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 predictive of which TB lineage they carry,<ref name="pmid16477032">{{cite journal | vauthors = Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, Nicol M, Niemann S, Kremer K, Gutierrez MC, Hilty M, Hopewell PC, Small PM | title = Variable host-pathogen compatibility in Mycobacterium tuberculosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 8 | pages = 2869–73 | date = February 2006 | pmid = 16477032 | pmc = 1413851 | doi = 10.1073/pnas.0511240103 | bibcode = 2006PNAS..103.2869G | doi-access = free }}</ref><ref name="pmid15041743">{{cite journal | vauthors = Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM | title = Stable association between strains of Mycobacterium tuberculosis and their human host populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 14 | pages = 4871–76 | date = April 2004 | pmid = 15041743 | pmc = 387341 | doi = 10.1073/pnas.0305627101 | doi-access = free }}</ref> which could reflect either a stable association between host populations and specific ''M. tuberculosis'' lineages and/or social interactions that are shaped by shared cultural and geographic histories. Regarding the congruence between human and ''M. tuberculosis'' phylogenies, a study relying on ''M. tuberculosis'' and human [[Y chromosome]] DNA sequences to formally assess the correlation between them, concluded that they are not congruent.<ref>{{cite journal | vauthors = Pepperell CS, Casto AM, Kitchen A, Granka JM, Cornejo OE, Holmes EC, Holmes EC, Birren B, Galagan J, Feldman MW | title = The role of selection in shaping diversity of natural M. tuberculosis populations | journal = PLOS Pathogens | volume = 9 | issue = 8 | pages = e1003543 | date = August 2013 | pmid = 23966858 | pmc = 3744410 | doi = 10.1371/journal.ppat.1003543 | doi-access = free }}</ref> Also, a more recent study which included genome sequences from ''M. tuberculosis'' complex members extracted from three 1,000-year-old Peruvian mummies, estimated that the [[most recent common ancestor]] of the ''M. tuberculosis'' complex lived only 4,000 – 6,000 years ago.<ref name=":2">{{cite journal | vauthors = Bos KI, Harkins KM, Herbig A, Coscolla M, Weber N, Comas I, Forrest SA, Bryant JM, Harris SR, Schuenemann VJ, Campbell TJ, Majander K, Wilbur AK, Guichon RA, Wolfe Steadman DL, Cook DC, Niemann S, Behr MA, Zumarraga M, Bastida R, Huson D, Nieselt K, Young D, Parkhill J, Buikstra JE, Gagneux S, Stone AC, Krause J | title = Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis | journal = Nature | volume = 514 | issue = 7523 | pages = 494–97 | date = October 2014 | pmid = 25141181 | pmc = 4550673 | doi = 10.1038/nature13591 | bibcode = 2014Natur.514..494B }}</ref> The ''M. tuberculosis'' evolutionary rate estimated by the Bos et al. study<ref name=":2" /> is also supported by a study on Lineage 4 relying on genomic [[Ancient DNA|aDNA]] sequences from Hungarian mummies more than 200 years old.<ref>{{cite journal | vauthors = Kay GL, Sergeant MJ, Zhou Z, Chan JZ, Millard A, Quick J, Szikossy I, Pap I, Spigelman M, Loman NJ, Achtman M, Donoghue HD, Pallen MJ | title = Eighteenth-century genomes show that mixed infections were common at time of peak tuberculosis in Europe | journal = Nature Communications | volume = 6 | issue = 1 | pages = 6717 | date = April 2015 | pmid = 25848958 | pmc = 4396363 | doi = 10.1038/ncomms7717 | bibcode = 2015NatCo...6.6717K }}</ref> 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 ''M. tuberculosis'' has occurred over the last 4,000–6,000 years.{{cn|date=May 2024}} Among the seven recognized lineages of ''M. tuberculosis'', 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.<ref name=":3">{{cite journal | vauthors = Brynildsrud OB, Pepperell CS, Suffys P, Grandjean L, Monteserin J, Debech N, Bohlin J, Alfsnes K, Pettersson JO, Kirkeleite I, Fandinho F, da Silva MA, Perdigao J, Portugal I, Viveiros M, Clark T, Caws M, Dunstan S, Thai PV, Lopez B, Ritacco V, Kitchen A, Brown TS, van Soolingen D, O'Neill MB, Holt KE, Feil EJ, Mathema B, Balloux F, Eldholm V | title = Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation | journal = Science Advances | volume = 4 | issue = 10 | pages = eaat5869 | date = October 2018 | pmid = 30345355 | pmc = 6192687 | doi = 10.1126/sciadv.aat5869 }}</ref> 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.<ref name=":2" /> Similarly, Lineage 4 was found to have spread from Europe to Africa during the [[Age of Discovery]], starting in the early 15th century.<ref name=":3" /> It has been suggested that ancestral mycobacteria may have infected early hominids in East Africa as early as three million years ago.<ref name="pmid16201017">{{cite journal | vauthors = Gutierrez MC, Brisse S, Brosch R, Fabre M, Omaïs B, Marmiesse M, Supply P, Vincent V | title = Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis | journal = PLOS Pathogens | volume = 1 | issue = 1 | pages = e5 | date = September 2005 | pmid = 16201017 | pmc = 1238740 | doi = 10.1371/journal.ppat.0010005 | doi-access = free }}</ref> DNA fragments from ''M. tuberculosis'' and tuberculosis disease indications were present in human bodies dating from 7000 BC found at [[Atlit-Yam]] in the [[Levant]].<ref>{{cite journal | vauthors = Hershkovitz I, Donoghue HD, Minnikin DE, Besra GS, Lee OY, Gernaey AM, Galili E, Eshed V, Greenblatt CL, Lemma E, Bar-Gal GK, Spigelman M | title = Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean | journal = PLOS ONE | volume = 3 | issue = 10 | pages = e3426 | date = 15 October 2008 | pmid = 18923677 | pmc = 2565837 | doi = 10.1371/journal.pone.0003426 | publisher = Public Library of Science (PLoS) | doi-access = free | bibcode = 2008PLoSO...3.3426H | veditors = Ahmed N }}</ref> ==Antibiotic resistance (ABR)== {{see also|Antimicrobial resistance}} ''M. tuberculosis'' is a clonal organism and does not exchange DNA via [[horizontal gene transfer]]. Despite an additionally slow evolution rate, the emergence and spread of antibiotic resistance in ''M. tuberculosis'' poses an increasing threat to global public health.<ref name="Eldholm & Balloux">{{cite journal | vauthors = Eldholm V, Balloux F | title = Antimicrobial Resistance in Mycobacterium tuberculosis: The Odd One Out | journal = Trends in Microbiology | volume = 24 | issue = 8 | pages = 637–648 | date = August 2016 | pmid = 27068531 | doi = 10.1016/j.tim.2016.03.007 | url = https://discovery.ucl.ac.uk/id/eprint/1482492/ | access-date = 23 December 2022 | archive-date = 28 September 2023 | archive-url = https://web.archive.org/web/20230928223359/https://discovery.ucl.ac.uk/id/eprint/1482492/ | url-status = live }}</ref> 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.<ref name=":5">{{Cite book |url=https://www.who.int/publications/i/item/9789240013131 |title=Global tuberculosis report 2020. |date=2020 |publisher=World Health Organization |isbn=978-92-4-001313-1 |oclc=1258341826 |access-date=4 April 2022 |archive-date=14 September 2022 |archive-url=https://web.archive.org/web/20220914120838/https://www.who.int/publications/i/item/9789240013131 |url-status=live }}</ref> Geographical discrepancies exist in the incidence rates of drug-resistant TB. Countries facing the highest rates of ABR TB China, India, Russia, and South Africa.<ref name=":5" /> Recent trends reveal an increase in drug-resistant cases in a number of regions, with Papua New Guinea, Singapore, and Australia undergoing significant increases.<ref>{{cite journal | vauthors = Ou ZJ, Yu DF, Liang YH, He WQ, Li YZ, Meng YX, Xiong HS, Zhang MY, He H, Gao YH, Wu F, Chen Q | title = Trends in burden of multidrug-resistant tuberculosis in countries, regions, and worldwide from 1990 to 2017: results from the Global Burden of Disease study | journal = Infectious Diseases of Poverty | volume = 10 | issue = 1 | pages = 24 | date = March 2021 | pmid = 33676581 | pmc = 7936417 | doi = 10.1186/s40249-021-00803-w | doi-access = free }}</ref> Multidrug-resistant Tuberculosis (MDR-TB) is characterised by resistance to at least the two front-line drugs [[isoniazid]] and [[rifampin]].<ref>{{cite journal |last1=Mousavi-Sagharchi |first1=Seyyed Mohammad Amin |last2=Afrazeh |first2=Elina |last3=Seyyedian-Nikjeh |first3=Seyyedeh Fatemeh |last4=Meskini |first4=Maryam |last5=Doroud |first5=Delaram |last6=Siadat |first6=Seyed Davar |title=New insight in molecular detection of Mycobacterium tuberculosis |journal=AMB Express |date=21 June 2024 |volume=14 |issue=1 |pages=74 |doi=10.1186/s13568-024-01730-3 |doi-access=free |pmid=38907086 |issn=2191-0855|pmc=11192714 }}</ref><ref name=":5" /> 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.<ref name=":5" /> Rifampin-resistance is primarily due to resistance-conferring mutations in the rifampin-resistance determining region (RRDR) within the rpoB gene.<ref>{{cite journal | vauthors = Zaw MT, Emran NA, Lin Z | title = Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis | journal = Journal of Infection and Public Health | volume = 11 | issue = 5 | pages = 605–610 | date = September 2018 | pmid = 29706316 | doi = 10.1016/j.jiph.2018.04.005 | s2cid = 14058414 | doi-access = free }}</ref> 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.<ref name=":6">{{cite journal | vauthors = Palomino JC, Martin A | title = Drug Resistance Mechanisms in Mycobacterium tuberculosis | journal = Antibiotics | volume = 3 | issue = 3 | pages = 317–340 | date = July 2014 | pmid = 27025748 | pmc = 4790366 | doi = 10.3390/antibiotics3030317 | doi-access = free }}</ref> This is encoded by the ''inhA'' 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.<ref name=":6" /> As MDR in ''M. tuberculosis'' 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 additional front-line drug.<ref name=":5" /> Thus, the development of alternative therapeutic measures is of utmost priority.{{cn|date=May 2024}} An intrinsic contributor to the antibiotic resistant nature of ''M. tuberculosis'' is its unique cell wall. Saturated with long-chain fatty acids or mycolic acids, the mycobacterial cell presents a robust, relatively insoluble barrier.<ref>{{cite journal | vauthors = Chalut C | title = MmpL transporter-mediated export of cell-wall associated lipids and siderophores in mycobacteria | journal = Tuberculosis | volume = 100 | pages = 32–45 | date = September 2016 | pmid = 27553408 | doi = 10.1016/j.tube.2016.06.004 }}</ref> 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 novel, promising therapeutic target is mycobacterial membrane protein large 3 (MmpL3).<ref name=":7">{{cite journal | vauthors = Xu Z, Meshcheryakov VA, Poce G, Chng SS | title = MmpL3 is the flippase for mycolic acids in mycobacteria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 30 | pages = 7993–7998 | date = July 2017 | pmid = 28698380 | pmc = 5544280 | doi = 10.1073/pnas.1700062114 | doi-access = free | bibcode = 2017PNAS..114.7993X | biorxiv = 10.1101/099440 }}</ref> 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.<ref name=":7" /> 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.<ref name=":7" /> The recently reported structure of MmpL3 revealed resistance-conferring mutations to associate primarily with the transmembrane domain.<ref name=":8">{{cite journal | vauthors = Adams O, Deme JC, Parker JL, Fowler PW, Lea SM, Newstead S | title = Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target | journal = Structure | volume = 29 | issue = 10 | pages = 1182–1191.e4 | date = October 2021 | pmid = 34242558 | pmc = 8752444 | doi = 10.1016/j.str.2021.06.013 }}</ref> Although resistance to pre-clinical MmpL3 inhibitors has been detected, analysis of the widespread mutational landscape revealed a low level of environmental resistance.<ref name=":8" /> 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.{{cn|date=May 2024}} ==Host genetics== 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.<ref>{{cite journal | vauthors = Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL | title = Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity | journal = Seminars in Immunology | volume = 26 | issue = 6 | pages = 454–70 | date = December 2014 | pmid = 25453225 | pmc = 4357480 | doi = 10.1016/j.smim.2014.09.008 }}</ref> 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.<ref>{{cite journal | vauthors = Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, Balabanova Y, Ehmen C, Muntau B, Ruge G, Sievertsen J, Gyapong J, Nikolayevskyy V, Hill PC, Sirugo G, Drobniewski F, van de Vosse E, Newport M, Alisjahbana B, Nejentsev S, Ottenhoff TH, Hill AV, Horstmann RD, Meyer CG | title = Common variants at 11p13 are associated with susceptibility to tuberculosis | journal = Nature Genetics | volume = 44 | issue = 3 | pages = 257–59 | date = February 2012 | pmid = 22306650 | pmc = 3427019 | doi = 10.1038/ng.1080 }}</ref><ref>{{cite journal|author-link26=Tumani Corrah | vauthors = Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, Sirugo G, Sisay-Joof F, Enimil A, Chinbuah MA, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Ngwira B, Teo YY, Small K, Rockett K, Kwiatkowski D, Fine PE, Hill PC, Newport M, Lienhardt C, Adegbola RA, Corrah T, Ziegler A, Morris AP, Meyer CG, Horstmann RD, Hill AV | title = Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2 | journal = Nature Genetics | volume = 42 | issue = 9 | pages = 739–41 | date = September 2010 | pmid = 20694014 | pmc = 4975513 | doi = 10.1038/ng.639 }}</ref> As is common in GWAS, the variants discovered have moderate effect sizes.{{cn|date=May 2024}} ==DNA repair== As an [[Intracellular parasite|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.<ref name=Boshoff>{{cite journal | vauthors = Boshoff HI, Reed MB, Barry CE, Mizrahi V | title = DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis | journal = Cell | volume = 113 | issue = 2 | pages = 183–93 | date = April 2003 | pmid = 12705867 | doi = 10.1016/s0092-8674(03)00270-8 | s2cid = 6273732 | doi-access = free }}</ref> Loss of this DNA polymerase reduces the virulence of ''M. tuberculosis'' in mice.<ref name=Boshoff /> 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 recombination]]al 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.<ref name=Brzostek>{{cite journal | vauthors = Brzostek A, Szulc I, Klink M, Brzezinska M, Sulowska Z, Dziadek J | title = Either non-homologous ends joining or homologous recombination is required to repair double-strand breaks in the genome of macrophage-internalized Mycobacterium tuberculosis | journal = PLOS ONE | volume = 9 | issue = 3 | pages = e92799 | year = 2014 | pmid = 24658131 | pmc = 3962454 | doi = 10.1371/journal.pone.0092799 | bibcode = 2014PLoSO...992799B | doi-access = free }}</ref> 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.<ref name=Brzostek /> However deficiency of DSB repair does not appear to impair ''M. tuberculosis'' virulence in animal models.<ref name="pmid24842925">{{cite journal | vauthors = Heaton BE, Barkan D, Bongiorno P, Karakousis PC, Glickman MS | title = Deficiency of double-strand DNA break repair does not impair Mycobacterium tuberculosis virulence in multiple animal models of infection | journal = Infection and Immunity | volume = 82 | issue = 8 | pages = 3177–85 | date = August 2014 | pmid = 24842925 | pmc = 4136208 | doi = 10.1128/IAI.01540-14 }}</ref> ==History== {{main|History of tuberculosis}} ''M. tuberculosis'', then known as the "[[Tubercle (anatomy)|tubercle]] [[bacillus]]", was first described on 24 March 1882 by [[Robert Koch]], who subsequently received the [[Nobel Prize in Physiology or Medicine]] for this discovery in 1905; the bacterium is also known as "Koch's bacillus".<ref>{{cite web |url=http://nobelprize.org/educational_games/medicine/tuberculosis/readmore.html |title=Robert Koch and Tuberculosis: Koch's Famous Lecture |publisher=Nobel Foundation |year=2008 |access-date=2008-11-18 |archive-date=28 February 2009 |archive-url=https://web.archive.org/web/20090228155136/http://nobelprize.org/educational_games/medicine/tuberculosis/readmore.html |url-status=live }}</ref><ref>{{Cite book|url=https://books.google.com/books?id=zoE9AQAAIAAJ&q=Charles+Darwin|title=Scientific American|date=1882-05-13|publisher=Munn & Company|pages=289|language=en|access-date=10 September 2021|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110204212/https://books.google.com/books?id=zoE9AQAAIAAJ&q=Charles+Darwin|url-status=live}}</ref> ''M. tuberculosis'' 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 [[Benjamin Marten]] described in his ''A Theory of Consumption'', tuberculosis may be caused by small living creatures transmitted through the air to other patients.<ref>{{cite web|url=http://www.mycobacteriumtuberculosis.net/history.html|title=Tuberculosis History Timeline|access-date=2010-06-18|url-status=dead|archive-url=https://web.archive.org/web/20100621125907/http://www.mycobacteriumtuberculosis.net/history.html|archive-date=21 June 2010|df=dmy-all}}</ref> ==Vaccine== 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.<ref>{{cite journal | vauthors = Herzmann C, Sotgiu G, Schaberg T, Ernst M, Stenger S, Lange C | title = Early BCG vaccination is unrelated to pulmonary immunity against Mycobacterium tuberculosis in adults | journal = The European Respiratory Journal | volume = 44 | issue = 4 | pages = 1087–1090 | date = October 2014 | pmid = 24969658 | doi = 10.1183/09031936.00086514 | s2cid = 12150010 | doi-access = free }}</ref> 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.<ref>{{Cite web|url=https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm|title=Fact Sheets {{!}} Infection Control & Prevention {{!}} Fact Sheet – BCG Vaccine {{!}} TB |publisher=CDC|date=2018-12-11|language=en-us|access-date=2019-11-12|archive-date=20 July 2013|archive-url=https://web.archive.org/web/20130720080800/http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm|url-status=live}}</ref> Research indicates there may be a correlation between BCG vaccination and better immune response to [[COVID-19]].<ref>{{Cite web|url=https://english.kyodonews.net/news/2020/04/3cd4a913c3cf-tuberculosis-vaccine-drawing-attention-in-fight-against-coronavirus.html|title=Tuberculosis vaccine drawing attention in fight against coronavirus|website=Kyodo News+|access-date=14 April 2020|archive-date=24 August 2022|archive-url=https://web.archive.org/web/20220824204320/https://english.kyodonews.net/news/2020/04/3cd4a913c3cf-tuberculosis-vaccine-drawing-attention-in-fight-against-coronavirus.html|url-status=live}}</ref> 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.<ref>{{Cite journal | vauthors = Anwar S, Qureshi J, Shahzad MI, Zaman M, Jilani A |date=2022 |title=DNA vaccine construct formation using Mycobacterium-specific gene Inh-A |journal=Journal of Preventive, Diagnostic and Treatment Strategies in Medicine |volume=1 |issue=3 |pages=192 |doi=10.4103/jpdtsm.jpdtsm_63_22 |issn=2949-6594 |doi-access=free }}</ref> == See also == * [[Philip D'Arcy Hart]] == References == {{Reflist}} == External links == {{Commons category|Mycobacterium tuberculosis}} {{Scholia|topic}} * [https://web.archive.org/web/20010302000815/http://www.tbdb.org/ TB database: an integrated platform for Tuberculosis research] * [https://web.archive.org/web/20180127083839/http://www.paediatric-surgery.net/2012/08/tuberculosis-photo-blog.html Photoblog about Tuberculosis] * {{cite web |title=''Mycobacterium tuberculosis'' |website=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser}} * [https://web.archive.org/web/20091201174847/http://tuberculist.epfl.ch/ Database on Mycobacterium tuberculosis genetics] {{Gram-positive actinobacteria diseases}} {{Taxonbar|from=Q130971}} {{Authority control}} [[Category:Acid-fast bacilli]] [[Category:Mycobacteria|tuberculosis]] [[Category:Tuberculosis]] [[Category:Pathogenic bacteria]] [[Category:Bacteria described in 1882]]'