Mycobacterium tuberculosis: Difference between revisions
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''M. tuberculosis'' divides every 15–20 hours, which is extremely slow compared to 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]] (e.g., [[mycolic acid]]), is likely responsible for this resistance and is a key virulence factor.<ref>{{cite book |author=Murray PR, Rosenthal KS, Pfaller MA | year=2005 | title=Medical Microbiology | publisher= Elsevier Mosby}}</ref> |
''M. tuberculosis'' divides every 15–20 hours, which is extremely slow compared to 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]] (e.g., [[mycolic acid]]), is likely responsible for this resistance and is a key virulence factor.<ref>{{cite book |author=Murray PR, Rosenthal KS, Pfaller MA | year=2005 | title=Medical Microbiology | publisher= Elsevier Mosby}}</ref> |
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When in the lungs, ''M. tuberculosis'' is taken up by alveolar [[macrophages]], but they are unable to digest and eradicate the bacterium. Its cell wall prevents the fusion of the [[phagosome]] with the [[lysosome]], which contains a host of anti-mycobacterial factors. Specifically, ''M. tuberculosis'' blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carry the ''UreC'' gene, which prevents acidification of the phagosome.<ref>{{cite journal | author = Bell E | title=Vaccines: A souped-up version of BCG | journal=Nature Reviews Immunology | volume=5 | issue=10 | pages=746 |date=October 2005| doi=10.1038/nri1720}}</ref> In addition, production of the diterpene [[Isotuberculosinol]] prevents maturation of the phagosome.<ref>{{cite doi|10.1021/ja9019287}}</ref> The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.<ref> |
When in the lungs, ''M. tuberculosis'' is taken up by alveolar [[macrophages]], but they are unable to digest and eradicate the bacterium. Its cell wall prevents the fusion of the [[phagosome]] with the [[lysosome]], which contains a host of anti-mycobacterial factors. Specifically, ''M. tuberculosis'' blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carry the ''UreC'' gene, which prevents acidification of the phagosome.<ref>{{cite journal | author = Bell E | title=Vaccines: A souped-up version of BCG | journal=Nature Reviews Immunology | volume=5 | issue=10 | pages=746 |date=October 2005| doi=10.1038/nri1720}}</ref> In addition, production of the diterpene [[Isotuberculosinol]] prevents maturation of the phagosome.<ref>{{cite doi|10.1021/ja9019287}}</ref> The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.<ref>{cite journal |author=Flynn JL, Chan J |title=Immune evasion by ''Mycobacterium tuberculosis'': living with the enemy |journal=Curr. Opin. Immunol. |volume=15 |issue=4 |pages=450–5 |date=August 2003 |pmid=12900278 |doi=10.1016/S0952-7915(03)00075-X |url=http://linkinghub.elsevier.com/retrieve/pii/S095279150300075X}}</ref> |
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The ability to construct ''M. tuberculosis'' mutants and test individual gene products for specific functions has significantly advanced our understanding of the [[pathogenesis]] and [[virulence factors]] of ''M. tuberculosis''. Many secreted and exported proteins are known to be important in pathogenesis.<ref name= WooldridgeK>{{cite book | |
The ability to construct ''M. tuberculosis'' mutants and test individual gene products for specific functions has significantly advanced our understanding of the [[pathogenesis]] and [[virulence factors]] of ''M. tuberculosis''. 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> |
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===Strain variation=== |
===Strain variation=== |
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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 that 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 disproved; on the other hand, if the bacteria are the same strain, then this supports (but does not definitively prove) the theory that B infected A. |
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 that 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 disproved; on the other hand, if the bacteria are the same strain, then this supports (but does not definitively prove) the theory that B infected A. |
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Until the early 2000s, ''M. tuberculosis'' strains were typed by [[pulsed field gel electrophoresis]] (PFGE).<ref>{{cite journal |author=Zhang Y, Mazurek GH, Cave MD, ''et al.'' |title=DNA polymorphisms in strains of ''Mycobacterium tuberculosis'' analyzed by pulsed-field gel electrophoresis: a tool for epidemiology |journal=J. Clin. Microbiol. |volume=30 |issue=6 |pages=1551–6 |date=June 1992 |pmid=1352518 |pmc=265327 |url=http://jcm.asm.org/cgi/pmidlookup?view=long&pmid=1352518}}}</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. |
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Until the early 2000s, ''M. tuberculosis'' strains were typed by [[pulsed field gel electrophoresis]] (PFGE).<ref>{{cite journal |
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| author = Y Zhang, G H Mazurek, M D Cave, ''et al.'' |
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| title = DNA polymorphisms in strains of ''Mycobacterium tuberculosis'' analyzed by pulsed-field gel electrophoresis: a tool for epidemiology |
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| journal = J Clin Microbiol |
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| year = 1992 |
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| volume = 30 |
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| issue = 6 |
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| pages = 1551–1556}}</ref><ref>{{cite journal |
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| title = Use of pulsed-field gel electrophoresis for molecular epidemiologic and population genetic studies of ''Mycobacterium tuberculosis'' |
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| author = Singh SP, Salamon H, Lahti CJ, Farid-Moyer M, Small PM. |
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| journal = J Clin Microbiol |
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| year = 1999 |
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| volume = 37 |
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| issue = 6 |
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| pages = 1927–31 |
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| pmid = 10325348 |
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| pmc=84986}}</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. |
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There are three generations of VNTR typing for ''M. tuberculosis''. The first scheme, called ETR (exact tandem repeat), used only five loci,<ref>{{cite journal |
There are three generations of VNTR typing for ''M. tuberculosis''. The first scheme, called ETR (exact tandem repeat), used only five loci,<ref>{{cite journal |
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| volume = 144 |
| volume = 144 |
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| issue = Pt 5 |
| issue = Pt 5 |
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| pages = |
| pages = 1189–96 |
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| pmid = 9611793 |
| pmid = 9611793 |
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| doi = 10.1099/00221287-144-5-1189}}</ref> but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called MIRU (mycobacterial interspersed repetitive unit) had discrimination as good as PFGE.<ref>{{cite journal |
| doi = 10.1099/00221287-144-5-1189}}</ref> but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called MIRU (mycobacterial interspersed repetitive unit) had discrimination as good as PFGE.<ref>{{cite journal |
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| volume = 98 |
| volume = 98 |
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| issue = 4 |
| issue = 4 |
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| pages = |
| pages = 1901–6 |
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| pmid = 11172048 |
| pmid = 11172048 |
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| doi=10.1073/pnas.98.4.1901 |
| doi=10.1073/pnas.98.4.1901 |
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| volume = 41 |
| volume = 41 |
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| issue = 8 |
| issue = 8 |
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| pages = |
| pages = 3514–20 |
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| pmid = 12904348 |
| pmid = 12904348 |
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| pmc=179797 |
| pmc=179797 |
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| volume = 44 |
| volume = 44 |
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| issue = 12 |
| issue = 12 |
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| pages = |
| pages = 4498–510 |
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| pmid = 17005759 |
| pmid = 17005759 |
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| doi=10.1128/JCM.01392-06 |
| doi=10.1128/JCM.01392-06 |
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The genome of the H37Rv strain was published in 1998.<ref>{{cite web |url=http://www.sanger.ac.uk/Projects/M_tuberculosis/ |title=''Mycobacterium tuberculosis'' |publisher=Sanger Institute |date=2007-03-29 |accessdate=2008-11-16}}</ref> Its size is 4 million base pairs, with 3959 genes; 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also six [[pseudogenes]]. |
The genome of the H37Rv strain was published in 1998.<ref>{{cite web |url=http://www.sanger.ac.uk/Projects/M_tuberculosis/ |title=''Mycobacterium tuberculosis'' |publisher=Sanger Institute |date=2007-03-29 |accessdate=2008-11-16}}</ref> Its size is 4 million base pairs, with 3959 genes; 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also six [[pseudogenes]]. |
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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 like fats and cholesterol. M. tuberculosis bacteria isolated from the lungs of infected mice were shown to preferentially utilize fatty acids over carbohydrate substrates.<ref>{{cite journal| |
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 like fats and cholesterol. M. tuberculosis bacteria isolated from the lungs of infected mice were shown to preferentially utilize fatty acids over carbohydrate substrates.<ref>{{cite journal |author=Bloch H, Segal W |title=Biochemical differentiation of ''Mycobacterium tuberculosis'' grown in vivo and in vitro |journal=J. Bacteriol. |volume=72 |issue=2 |pages=132–41 |date=August 1956 |pmid=13366889 |pmc=357869 |url=http://jb.asm.org/cgi/pmidlookup?view=long&pmid=13366889}}</ref> M. tuberculosis can also grow on the lipid [[cholesterol]] as a sole source of carbon, and genes involved in the cholesterol utilization pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis.<ref>{{cite journal|last1=Wipperman|first1=Matthew, F.|last2=Thomas|first2=Suzanne, T.|last3=Sampson|first3=Nicole, S.|title=Pathogen roid rage: Cholesterol utilization by Mycobacterium tuberculosis|journal=Crit. Rev. Biochem. Mol. Biol.|date=2014|doi=10.3109/10409238.2014.895700|pmid=24611808|url=http://informahealthcare.com/doi/abs/10.3109/10409238.2014.895700}}</ref> |
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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 |author=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|url=http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(01)00236-7}}</ref> |
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 |author=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|url=http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(01)00236-7}}</ref> |
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[[Mycobacterium tuberculosis sRNA|Nine noncoding sRNAs]] have been characterised in ''M. tuberculosis'',<ref>{{cite journal |author=Arnvig KB, Young DB |title=Identification of small RNAs in ''Mycobacterium tuberculosis'' |journal=Mol. Microbiol. |volume=73 |issue=3 |pages=397–408 |date=August 2009 |pmid=19555452 |pmc=2764107 |doi=10.1111/j.1365-2958.2009.06777.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0950-382X&date=2009&volume=73&issue=3&spage=397 |
[[Mycobacterium tuberculosis sRNA|Nine noncoding sRNAs]] have been characterised in ''M. tuberculosis'',<ref>{{cite journal |author=Arnvig KB, Young DB |title=Identification of small RNAs in ''Mycobacterium tuberculosis'' |journal=Mol. Microbiol. |volume=73 |issue=3 |pages=397–408 |date=August 2009 |pmid=19555452 |pmc=2764107 |doi=10.1111/j.1365-2958.2009.06777.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0950-382X&date=2009&volume=73&issue=3&spage=397 }}</ref> with a further 56 predicted in a [[bioinformatics]] screen.<ref>{{cite journal |author=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 Res. |volume=34 |issue=12 |pages=3484–93 |year=2006 |pmid=16870723 |pmc=1524904 |doi=10.1093/nar/gkl453 |url=http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16870723 }}</ref> |
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In 2013, a study on the genome of several sensitive, ultra-resistant 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 that some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role that the intergenic regions in the development of this resistance, and that most of the genes that are proposed in this study to be responsible for drug resistance have an essential role in the development of ''M. tuberculosis''.<ref>Zhang H et al. Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. |
In 2013, a study on the genome of several sensitive, ultra-resistant 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 that some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role that the intergenic regions in the development of this resistance, and that most of the genes that are proposed in this study to be responsible for drug resistance have an essential role in the development of ''M. tuberculosis''.<ref>{{cite journal |author=Zhang H, Li D, Zhao L, ''et al.'' |title=Genome sequencing of 161 ''Mycobacterium tuberculosis'' isolates from China identifies genes and intergenic regions associated with drug resistance |journal=Nat. Genet. |volume=45 |issue=10 |pages=1255–60 |date=October 2013 |pmid=23995137 |doi=10.1038/ng.2735 }}</ref> |
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==Evolution== |
==Evolution== |
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The ''Mycobacterium tuberculosis'' complex evolved in [[Africa]] and most probably in the Horn of Africa.<ref name=Blouin2012>Blouin Y, Hauck Y, Soler C, |
The ''Mycobacterium tuberculosis'' complex evolved in [[Africa]] and most probably in the Horn of Africa.<ref name=Blouin2012>{{cite journal |author=Blouin Y, Hauck Y, Soler C, ''et al.'' |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 |url=http://dx.plos.org/10.1371/journal.pone.0052841}}</ref> The ''M. tuberculosis'' group has a number of members that include ''[[Mycobacterium africanum]]'', ''[[Mycobacterium bovis]]'' (Dassie's bacillus), ''[[Mycobacterium caprae]]'', ''[[Mycobacterium microti]]'', Mycobacterium mungi, Mycobacterium orygis and ''[[Mycobacterium pinnipedii]]''. This group may also include the Mycobacterium canettii clade. |
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The ''M. canettii'' clade — which includes ''Mycobacterium prototuberculosis'' — are 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 ''Mycobacterium tuberculosis'' appears to be the species ''Mycobacterium canettii'', first described in 1969.<ref name=Blouin2014>Blouin Y, Cazajous G, Dehan C, |
The ''M. canettii'' clade — which includes ''Mycobacterium prototuberculosis'' — are 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 ''Mycobacterium tuberculosis'' appears to be the species ''Mycobacterium canettii'', first described in 1969.<ref name=Blouin2014>{{cite journal |author=Blouin Y, Cazajous G, Dehan C, ''et al.'' |title=Progenitor ''Mycobacterium canettii'' clone responsible for lymph node tuberculosis epidemic, Djibouti |journal=Emerging Infect. Dis. |volume=20 |issue=1 |pages=21–8 |date=January 2014 |pmid=24520560 |pmc=3884719 }}</ref> |
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The established members of the ''M. tuberculosis'' complex are all clonal in their spread. The main human infecting species have been classified into seven spoligotypes: type 1 contains the [[East Africa]]n-[[India]]n (EAI) and some Manu (Indian) strains; type 2 is the [[Beijing]] group; type 3 consists of the [[Central Asia]]n (CAS) strains; type 4 of the [[Ghana]] and [[Haarlem]] (H/T), [[Latin America]]-[[Mediterranean]] (LAM) and X strains; types 5 and 6 correspond to ''Mycobacterium africanum'' and are observed predominantly and at very high frequency 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. |
The established members of the ''M. tuberculosis'' complex are all clonal in their spread. The main human infecting species have been classified into seven spoligotypes: type 1 contains the [[East Africa]]n-[[India]]n (EAI) and some Manu (Indian) strains; type 2 is the [[Beijing]] group; type 3 consists of the [[Central Asia]]n (CAS) strains; type 4 of the [[Ghana]] and [[Haarlem]] (H/T), [[Latin America]]-[[Mediterranean]] (LAM) and X strains; types 5 and 6 correspond to ''Mycobacterium africanum'' and are observed predominantly and at very high frequency 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. |
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Type 2 and 3 are more closely related to each other than to the other types. Types 5 and 6 are most closely aligned with the species that do not normally infect humans. Type 3 has been divided into two clades: CAS-Kili (found in [[Tanzania]]) and CAS-Delhi (found in India and [[Saudi Arabia]]). |
Type 2 and 3 are more closely related to each other than to the other types. Types 5 and 6 are most closely aligned with the species that do not normally infect humans. Type 3 has been divided into two clades: CAS-Kili (found in [[Tanzania]]) and CAS-Delhi (found in India and [[Saudi Arabia]]). |
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The [[most recent common ancestor]] of the ''M. tuberculosis'' complex evolved ~40,000 years ago.<ref name=Wirth2008>Wirth T, Hildebrand F, Allix- |
The [[most recent common ancestor]] of the ''M. tuberculosis'' complex evolved ~40,000 years ago.<ref name=Wirth2008>{{cite journal |author=Wirth T, Hildebrand F, Allix-Béguec C, ''et al.'' |title=Origin, spread and demography of the ''Mycobacterium tuberculosis'' complex |journal=PLoS Pathog. |volume=4 |issue=9 |pages=e1000160 |year=2008 |pmid=18802459 |pmc=2528947 |doi=10.1371/journal.ppat.1000160 |url=http://dx.plos.org/10.1371/journal.ppat.1000160}}</ref> The most recent common ancestor of the EAI and LAM strains has been estimated to be 13,700 and 7,000 years ago respectively. The Beijing- CAS strains diverged ~17,100 years ago. All types of the ''M. tuberculosis'' began their current expansion ~5000 years ago—a period that coincides with the appearance of ''Mycobacterium bovis''. The Beijing strain appears to have been the most successful with a ~500 increase in [[effective population size]] (N<sub>e</sub>) since its expansion began. The least successful of the main lineages appears to have been those limited to Africa where they have undergone an N<sub>e</sub> increase of only 5 fold. Since its initial evolution ''M. bovis'' has undergone an expansion of N<sub>e</sub> of ~65 fold. |
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==History== |
==History== |
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* [http://tbdb.org TB database: an integrated platform for Tuberculosis research] |
* [http://tbdb.org TB database: an integrated platform for Tuberculosis research] |
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* [http://www.paediatric-surgery.net/2012/08/tuberculosis-photo-blog.html Photoblog about Tuberculosis] |
* [http://www.paediatric-surgery.net/2012/08/tuberculosis-photo-blog.html Photoblog about Tuberculosis] |
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* {{cite web |title=''Mycobacterium tuberculosis'' |work=NCBI Taxonomy Browser |url=http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=1773 |id=1773}} |
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{{Commons category|Mycobacterium tuberculosis}} |
{{Commons category|Mycobacterium tuberculosis}} |
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Revision as of 07:13, 16 August 2014
| Mycobacterium tuberculosis | |
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| M. tuberculosis bacterial colonies | |
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| Species: | M. tuberculosis
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| Binomial name | |
| Mycobacterium tuberculosis Zopf 1883
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| Synonyms | |
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Tubercle bacillus Koch 1882 | |
Mycobacterium tuberculosis (MTB) is a pathogenic bacterial species in the family Mycobacteriaceae and the causative agent of most cases of tuberculosis (TB).[1] 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), which makes the cells impervious to Gram staining. The Ziehl-Neelsen stain, or acid-fast stain, is used instead. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, MTB infects the lungs. The most frequently used diagnostic methods for TB are the tuberculin skin test, acid-fast stain, and chest radiographs.[1]
The M. tuberculosis genome was sequenced in 1998.[2][3]
Pathophysiology
M. tuberculosis requires oxygen to grow. It does not retain any bacteriological stain due to high lipid content in its wall, hence Ziehl-Neelsen staining, or acid-fast staining, is used. Despite this, it is considered a Gram-positive bacteria. While mycobacteria do not seem to fit the Gram-positive category from an empirical standpoint (i.e., they do not retain the crystal violet stain), they are classified as acid-fast Gram-positive bacteria due to their lack of an outer cell membrane.[1]
M. tuberculosis divides every 15–20 hours, which is extremely slow compared to other bacteria, which tend to have division times measured in minutes (Escherichia coli can divide roughly every 20 minutes). It is a small bacillus that can withstand weak disinfectants and can survive in a dry state for weeks. Its unusual cell wall, rich in lipids (e.g., mycolic acid), is likely responsible for this resistance and is a key virulence factor.[4]
When in the lungs, M. tuberculosis is taken up by alveolar macrophages, but they are unable to digest and eradicate the bacterium. Its cell wall prevents the fusion of the phagosome with the lysosome, which contains a host of anti-mycobacterial factors. Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carry the UreC gene, which prevents acidification of the phagosome.[5] In addition, production of the diterpene Isotuberculosinol prevents maturation of the phagosome.[6] The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.[7]
The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced our understanding of the pathogenesis and virulence factors of M. tuberculosis. Many secreted and exported proteins are known to be important in pathogenesis.[8]
Strain variation
M. tuberculosis is genetically diverse, which results in significant phenotypic differences between clinical isolates. Different strains of M. tuberculosis are associated with different geographic regions. However, phenotypic studies suggest that strain variation never has implications for the development of new diagnostics and vaccines. Microevolutionary variation does affect the relative fitness and transmission dynamics of antibiotic-resistant strains.[9]
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 that 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 disproved; on the other hand, if the bacteria are the same strain, then this supports (but does not definitively prove) the theory that B infected A.
Until the early 2000s, M. tuberculosis strains were typed by pulsed field gel electrophoresis (PFGE).[10] This has now been superseded by 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.
There are three generations of VNTR typing for M. tuberculosis. The first scheme, called ETR (exact tandem repeat), used only five loci,[11] but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called MIRU (mycobacterial interspersed repetitive unit) had discrimination as good as PFGE.[12][13] The third generation (MIRU2) 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.[14]
Hypervirulent strains
Mycobacterium outbreaks are often caused by hypervirulent strains of M. tuberculosis. In laboratory experiments, these clinical isolates elicit unusual immunopathology, and may be either hyperinflammatory or hypoinflammatory. Studies have shown the majority of hypervirulent mutants have deletions in their cell wall-modifying enzymes or regulators that respond to environmental stimuli. Studies of these mutants have indicated the mechanisms that enable M. tuberculosis to mask its full pathogenic potential, inducing a granuloma that provides a protective niche, and enable the bacilli to sustain a long-term, persistent infection.[15]
Microscopy
M. tuberculosis is characterized by caseating granulomas containing Langhans giant cells, which have a "horseshoe" pattern of nuclei. Organisms are identified by their red color on acid-fast staining.
Genome
The genome of the H37Rv strain was published in 1998.[16] Its size is 4 million base pairs, with 3959 genes; 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also six pseudogenes.
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 like fats and cholesterol. M. tuberculosis bacteria isolated from the lungs of infected mice were shown to preferentially utilize fatty acids over carbohydrate substrates.[17] M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol utilization pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis.[18]
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.[19]
Nine noncoding sRNAs have been characterised in M. tuberculosis,[20] with a further 56 predicted in a bioinformatics screen.[21]
In 2013, a study on the genome of several sensitive, ultra-resistant 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 that some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role that the intergenic regions in the development of this resistance, and that most of the genes that are proposed in this study to be responsible for drug resistance have an essential role in the development of M. tuberculosis.[22]
Evolution
The Mycobacterium tuberculosis complex evolved in Africa and most probably in the Horn of Africa.[23] The M. tuberculosis group has a number of members that include Mycobacterium africanum, Mycobacterium bovis (Dassie's bacillus), Mycobacterium caprae, Mycobacterium microti, Mycobacterium mungi, Mycobacterium orygis and Mycobacterium pinnipedii. This group may also include the Mycobacterium canettii clade.
The M. canettii clade — which includes Mycobacterium prototuberculosis — are 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 Mycobacterium tuberculosis appears to be the species Mycobacterium canettii, first described in 1969.[24]
The established members of the M. tuberculosis complex are all clonal in their spread. The main human infecting species have been classified into seven spoligotypes: type 1 contains the East African-Indian (EAI) and some Manu (Indian) strains; type 2 is the Beijing group; type 3 consists of the Central Asian (CAS) strains; type 4 of the Ghana and Haarlem (H/T), Latin America-Mediterranean (LAM) and X strains; types 5 and 6 correspond to Mycobacterium africanum and are observed predominantly and at very high frequency in West Africa. A seventh type has been isolated from the Horn of Africa.[23] The other species of this complex belong to a number of spoligotypes and do not normally infect humans.
Type 2 and 3 are more closely related to each other than to the other types. Types 5 and 6 are most closely aligned with the species that do not normally infect humans. Type 3 has been divided into two clades: CAS-Kili (found in Tanzania) and CAS-Delhi (found in India and Saudi Arabia).
The most recent common ancestor of the M. tuberculosis complex evolved ~40,000 years ago.[25] The most recent common ancestor of the EAI and LAM strains has been estimated to be 13,700 and 7,000 years ago respectively. The Beijing- CAS strains diverged ~17,100 years ago. All types of the M. tuberculosis began their current expansion ~5000 years ago—a period that coincides with the appearance of Mycobacterium bovis. The Beijing strain appears to have been the most successful with a ~500 increase in effective population size (Ne) since its expansion began. The least successful of the main lineages appears to have been those limited to Africa where they have undergone an Ne increase of only 5 fold. Since its initial evolution M. bovis has undergone an expansion of Ne of ~65 fold.
History
M. tuberculosis, then known as the "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".[26]
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 that are transmitted through the air to other patients.[27]
Vaccine
The BCG vaccine has been developed with success in preventing tuberculosis.
See also
References
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{{cite book}}:|author=has generic name (help) - ^ Cole ST, Brosch R, Parkhill J; et al. (June 1998). "Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence". Nature. 393 (6685): 537–44. doi:10.1038/31159. PMID 9634230.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Murray PR, Rosenthal KS, Pfaller MA (2005). Medical Microbiology. Elsevier Mosby.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Bell E (October 2005). "Vaccines: A souped-up version of BCG". Nature Reviews Immunology. 5 (10): 746. doi:10.1038/nri1720.
- ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/ja9019287, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Zhang H, Li D, Zhao L; et al. (October 2013). "Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance". Nat. Genet. 45 (10): 1255–60. doi:10.1038/ng.2735. PMID 23995137.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ a b Blouin Y, Hauck Y, Soler C; et al. (2012). "Significance of the identification in the Horn of Africa of an exceptionally deep branching Mycobacterium tuberculosis clade". PLoS ONE. 7 (12): e52841. doi:10.1371/journal.pone.0052841. PMC 3531362. PMID 23300794.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Blouin Y, Cazajous G, Dehan C; et al. (January 2014). "Progenitor Mycobacterium canettii clone responsible for lymph node tuberculosis epidemic, Djibouti". Emerging Infect. Dis. 20 (1): 21–8. PMC 3884719. PMID 24520560.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Wirth T, Hildebrand F, Allix-Béguec C; et al. (2008). "Origin, spread and demography of the Mycobacterium tuberculosis complex". PLoS Pathog. 4 (9): e1000160. doi:10.1371/journal.ppat.1000160. PMC 2528947. PMID 18802459.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ "Robert Koch and Tuberculosis: Koch's Famous Lecture". Nobel Foundation. 2008. Retrieved 18 November 2008.
- ^ "Tuberculosis History Timeline". Retrieved 18 June 2010.
External links
- TB database: an integrated platform for Tuberculosis research
- Photoblog about Tuberculosis
- "Mycobacterium tuberculosis". NCBI Taxonomy Browser. 1773.
