|M. tuberculosis bacterial colonies|
Tubercle bacillus Koch 1882
Mycobacterium tuberculosis is a pathogenic bacterial species in the family Mycobacteriaceae and the causative agent of most cases of tuberculosis. 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, it infects the lungs. The most frequently used in diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, and chest radiographs.
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 bacterium. 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.
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.
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 antimycobacterial 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. In addition, production of the diterpene isotuberculosinol prevents maturation of the phagosome. The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.
The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced the understanding of the pathogenesis and virulence factors of M. tuberculosis. Many secreted and exported proteins are known to be important in pathogenesis. Aerolysin is a virulence factor of the pathogenic bacterium Aeromonas hydrophila. Resistant strains of mycobacterium tuberculosis have developed resistance to more than one TB drug, due to mutations in their genes.
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 the 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.
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 disproved; however, if the bacteria are the same strain, then this supports (but does not definitively prove) the theory that B infected A. ASIANSS
Until the early 2000s, M. tuberculosis strains were typed by pulsed field gel electrophoresis (PFGE). 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.
Three generations of VNTR typing for M. tuberculosis are noted. The first scheme, called exact tandem repeat, used only five loci, but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called mycobacterial interspersed repetitive unit, had discrimination as good as PFGE. The third generation (mycobacterial 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.
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. The majority of hypervirulent mutants have deletions in their cell wall-modifying enzymes or regulators that respond to environmental stimuli. The mechanisms that enable M. tuberculosis to mask its full pathogenic potential, inducing a granuloma that provides a protective niche, enable the bacilli to sustain a long-term, persistent infection.
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.
The genome of the H37Rv strain was published in 1998. 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 such as fats and cholesterol. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates. 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.
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.
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.
The M. tuberculosis complex evolved in Africa and most probably in the Horn of Africa. 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 — 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 Mycobacterium tuberculosis appears to be the species Mycobacterium canettii, first described in 1969.
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. The other species of this complex belong to a number of spoligotypes and do not normally infect humans.
Types 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. 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 about 17,100 years ago. All types of the M. tuberculosis began their current expansion about 5000 years ago—a period that coincides with the appearance of M. bovis. The Beijing strain appears to have been the most successful with around a 500-fold 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 five-fold. Since its initial evolution, M. bovis has undergone an expansion of Ne of about 65-fold.
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".
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.
The BCG vaccine has had success in preventing tuberculosis.
- Ismael Kassim, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
- 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.
- Camus JC, Pryor MJ, Médigue C, Cole ST (October 2002). "Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv". Microbiology (Reading, Engl.) 148 (Pt 10): 2967–73. PMID 12368430.
- Murray PR, Rosenthal KS, Pfaller MA (2005). Medical Microbiology. Elsevier Mosby.
- Bell E (October 2005). "Vaccines: A souped-up version of BCG". Nature Reviews Immunology 5 (10): 746. doi:10.1038/nri1720.
- Mann, F. M.; Xu, M.; Chen, X.; Fulton, D. B.; Russell, D. G.; Peters, R. J. (2009). "Edaxadiene: A New Bioactive Diterpene fromMycobacterium tuberculosis". Journal of the American Chemical Society 131 (48): 17526–17527. doi:10.1021/ja9019287. PMC 2787244. PMID 19583202.
- Flynn JL, Chan J (August 2003). "Immune evasion by Mycobacterium tuberculosis: living with the enemy". Curr. Opin. Immunol. 15 (4): 450–5. doi:10.1016/S0952-7915(03)00075-X. PMID 12900278.
- Wooldridge K, ed. (2009). Bacterial Secreted Proteins: Secretory Mechanisms and Role in Pathogenesis. Caister Academic Press. ISBN 978-1-904455-42-4.
- Gagneux S (2009). "Strain variation and evolution". In Parish T, Brown A. Mycobacterium: Genomics and Molecular Biology. Caister Academic Press. ISBN 978-1-904455-40-0.
- Zhang Y, Mazurek GH, Cave MD, et al. (June 1992). "DNA polymorphisms in strains of Mycobacterium tuberculosis analyzed by pulsed-field gel electrophoresis: a tool for epidemiology". J. Clin. Microbiol. 30 (6): 1551–6. PMC 265327. PMID 1352518.}
- Frothingham R, Meeker-O'Connell WA. (1998). "Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats". Microbiology 144 (Pt 5): 1189–96. doi:10.1099/00221287-144-5-1189. PMID 9611793.
- Mazars E, Lesjean S, Banuls AL, et al. (2001). "High-resolution minisatellite-based typing as a portable approach to global analysis of Mycobacterium tuberculosis molecular epidemiology". Proc Natl Acad Sci U S A 98 (4): 1901–6. doi:10.1073/pnas.98.4.1901. PMC 29354. PMID 11172048.
- Hawkey PM, Smith EG, Evans JT, et al. (2003). "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". J Clin Microbiol 41 (8): 3514–20. doi:10.1128/JCM.41.8.3514-3520.2003. PMC 179797. PMID 12904348.
- Supply P, Allix C, Lesjean S, et al. (2006). "Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis". J Clin Microbiol 44 (12): 4498–510. doi:10.1128/JCM.01392-06. PMC 1698431. PMID 17005759.
- Casali N (2009). "Hypervirulent Mycobacterium tuberculosis". Mycobacterium: Genomics and Molecular Biology. Caister Academic Press. ISBN 978-1-904455-40-0.
- "Mycobacterium tuberculosis". Sanger Institute. 2007-03-29. Retrieved 2008-11-16.
- Bloch H, Segal W (August 1956). "Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro". J. Bacteriol. 72 (2): 132–41. PMC 357869. PMID 13366889.
- Wipperman, Matthew, F.; Thomas, Suzanne, T.; Sampson, Nicole, S. (2014). "Pathogen roid rage: Cholesterol utilization by Mycobacterium tuberculosis". Crit. Rev. Biochem. Mol. Biol. doi:10.3109/10409238.2014.895700. PMID 24611808.
- Glickman MS, Jacobs WR (February 2001). "Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline". Cell 104 (4): 477–85. doi:10.1016/S0092-8674(01)00236-7. PMID 11239406.
- Arnvig KB, Young DB (August 2009). "Identification of small RNAs in Mycobacterium tuberculosis". Mol. Microbiol. 73 (3): 397–408. doi:10.1111/j.1365-2958.2009.06777.x. PMC 2764107. PMID 19555452.
- Livny J, Brencic A, Lory S, Waldor MK (2006). "Identification of 17 Pseudomonas aeruginosa sRNAs and prediction of sRNA-encoding genes in 10 diverse pathogens using the bioinformatic tool sRNAPredict2". Nucleic Acids Res. 34 (12): 3484–93. doi:10.1093/nar/gkl453. PMC 1524904. PMID 16870723.
- 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.
- 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.
- 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.
- 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.
- "Robert Koch and Tuberculosis: Koch's Famous Lecture". Nobel Foundation. 2008. Retrieved 2008-11-18.
- "Tuberculosis History Timeline". Retrieved 2010-06-18.
- TB database: an integrated platform for Tuberculosis research
- Photoblog about Tuberculosis
- "Mycobacterium tuberculosis". NCBI Taxonomy Browser. 1773.
|Wikimedia Commons has media related to Mycobacterium tuberculosis.|