The Mycobacterium tuberculosis complex (MTBC) evolved from an environmental organism to an obligate pathogen through a combination of genome reduction and the acquisition of new genes. Key steps in this process were acquiring the ability to grow inside host cells and the ability to transmit directly from host to host.
Data indicate that the transition from environmental organism to an obligate pathogen happened in Africa, but there is currently no consensus with respect to the timing of this event.
The MTBC comprises human-adapted and animal-adapted lineages, but the molecular basis of host preference remains largely unknown.
Among the human-adapted MTBC lineages, some occur globally and others are geographically restricted, suggesting generalist and specialist phenotypes.
Most evidence indicates that ongoing horizontal gene exchange in the MTBC is absent. As a consequence, the MTBC exhibits a clonal population structure.
Strict clonality combined with serial transmission bottlenecks leads to a reduction in MTBC genomic diversity and affects the balance between natural selection and random genetic drift.
The global epidemics of antibiotic-resistant MTBC are driven by both the de novo acquisition of resistance mutations during suboptimal patient treatment and direct transmission of resistant strains between individuals.
Tuberculosis (TB) is the number one cause of human death due to an infectious disease. The causative agents of TB are a group of closely related bacteria known as the Mycobacterium tuberculosis complex (MTBC). As the MTBC exhibits a clonal population structure with low DNA sequence diversity, methods (such as multilocus sequence typing) that are applied to more genetically diverse bacteria are uninformative, and much of the ecology and evolution of the MTBC has therefore remained unknown. Owing to recent advances in whole-genome sequencing and analyses of large collections of MTBC clinical isolates from around the world, many new insights have been gained, including a better understanding of the origin of the MTBC as an obligate pathogen and its molecular evolution and population genetic characteristics both within and between hosts, as well as many aspects related to antibiotic resistance. The purpose of this Review is to summarize these recent discoveries and discuss their relevance for developing better tools and strategies to control TB.
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Paulson, T. Epidemiology: a mortal foe. Nature 502, S2–S3 (2013).
World Health Organization. Global tuberculosis control — surveillance, planning, financing. (WHO, Geneva, Switzerland, 2017).
Houben, R. M. & Dodd, P. J. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLOS Med. 13, e1002152 (2016).
Dheda, K., Barry, C. E. III & Maartens, G. Tuberculosis. Lancet 387, 1211–1226 (2016).
Dye, C., Williams, B. G., Espinal, M. A. & Raviglione, M. C. Erasing the world's slow stain: strategies to beat multidrug-resistant tuberculosis. Science 295, 2042–2046 (2002).
Comas, I. & Gagneux, S. The past and future of tuberculosis research. PLOS Pathog. 5, e1000600 (2009).
Achtman, M. Evolution, population structure, and phylogeography of genetically monomorphic bacterial pathogens. Annu. Rev. Microbiol. 62, 53–70 (2008).
Gagneux, S. Strain variation in the Mycobacterium tuberculosis complex: its role in biology, epidemiology and control (Springer, Heidelberg, 2017).
Fedrizzi, T. et al. Genomic characterization of Nontuberculous Mycobacteria. Sci. Rep. 7, 45258 (2017).
Rogall, T., Wolters, J., Flohr, T. & Bottger, E. C. Towards a phylogeny and definition of species at the molecular level within the genus Mycobacterium. Int. J. Syst. Bacteriol. 40, 323–330 (1990).
Brites, D. & Gagneux, S. Old and new selective pressures on Mycobacterium tuberculosis. Infect. Genet. Evol. 12, 678–685 (2012).
Ebert, D. & Bull, J. J. Challenging the trade-off model for the evolution of virulence: is virulence management feasible? Trends Microbiol. 11, 15–20 (2003).
Jang, J., Becq, J., Gicquel, B., Deschavanne, P. & Neyrolles, O. Horizontally acquired genomic islands in the tubercle bacilli. Trends Microbiol. 16, 303–308 (2008).
VanderVen, B. C., Huang, L., Rohde, K. H. & Russell, D. G. The minimal unit of infection: Mycobacterium tuberculosis in the macrophage. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.TBTB2-0025-2016 (2016).
Chisholm, R. H., Trauer, J. M., Curnoe, D. & Tanaka, M. M. Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis. Proc. Natl Acad. Sci. USA 113, 9051–9056 (2016).
Veyrier, F. J., Dufort, A. & Behr, M. A. The rise and fall of the Mycobacterium tuberculosis genome. Trends Microbiol. 19, 156–161 (2011).
Stinear, T. P. et al. Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res. 18, 729–741 (2008).
Wang, J. et al. Insights on the emergence of Mycobacterium tuberculosis from the analysis of Mycobacterium kansasii. Genome Biol. Evol. 7, 856–870 (2015).
Becq, J. et al. Contribution of horizontally acquired genomic islands to the evolution of the Tubercle Bacilli. Mol. Biol. Evol. 24, 1861–1871 (2007).
Veyrier, F., Pletzer, D., Turenne, C. & Behr, M. A. Phylogenetic detection of horizontal gene transfer during the step-wise genesis of Mycobacterium tuberculosis. BMC Evol. Biol. 9, 196 (2009).
Reva, O., Korotetskiy, I. & Ilin, A. Role of the horizontal gene exchange in evolution of pathogenic Mycobacteria. BMC Evol. Biol. 15 (Suppl. 1), S2 (2015).
Boritsch, E. C. et al. A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent. Mol. Microbiol. 93, 835–852 (2014).
Brennan, M. J. & Delogu, G. The PE multigene family: a 'molecular mantra' for mycobacteria. Trends Microbiol. 10, 246–249 (2002).
Gey van Pittius, N. C. et al. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol. Biol. 6, 95 (2006).
Sala, A., Bordes, P. & Genevaux, P. Multiple toxin-antitoxin systems in Mycobacterium tuberculosis. Toxins (Basel) 6, 1002–1020 (2014).
Rose, G. et al. Mapping of genotype-phenotype diversity among clinical isolates of Mycobacterium tuberculosis by sequence-based transcriptional profiling. Genome Biol. Evol. 5, 1849–1862 (2013).
Ernst, J. D. The immunological life cycle of tuberculosis. Nat. Rev. Immunol. 12, 581–591 (2012).
Gutierrez, C. et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLOS Pathog. 1, 1–7 (2005).
Blouin, Y. et al. Progenitor “Mycobacterium canettii” clone responsible for lymph node tuberculosis epidemic, Djibouti. Emerg. Infect. Dis. 20, 21–28 (2014).
Koeck, J. L. et al. Clinical characteristics of the smooth tubercle bacilli “Mycobacterium canettii” infection suggest the existence of an environmental reservoir. Clin. Microbiol. Infect. 17, 1013–1019 (2010).
Supply, P. et al. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis. Nat. Genet. 45, 172–179 (2013). This is the most detailed genomic analysis of M. canettii and other STB to date and provides interesting insights into the evolution of the MTBC.
Coscolla, M. & Gagneux, S. Consequences of genomic diversity in Mycobacterium tuberculosis. Semin. Immunol. 26, 431–444 (2014).
Smith, S. E. et al. Comparative genomic and phylogenetic approaches to characterize the role of genetic recombination in mycobacterial evolution. PLOS One 7, e50070 (2012).
Gray, T. A., Krywy, J. A., Harold, J., Palumbo, M. J. & Derbyshire, K. M. Distributive conjugal transfer in mycobacteria generates progeny with meiotic-like genome-wide mosaicism, allowing mapping of a mating identity locus. PLOS Biol. 11, e1001602 (2013). This paper is the first description of the novel mechanism of horizontal gene exchange known as distributive conjugal transfer.
Mortimer, T. D. & Pepperell, C. S. Genomic signatures of distributive conjugal transfer among mycobacteria. Genome Biol. Evol. 6, 2489–2500 (2014).
Boritsch, E. C. et al. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc. Natl Acad. Sci. USA 113, 9876–9881 (2016). This paper provides experimental evidence for ongoing HGT in M. canettii and other STB. By contrast, and despite multiple attempts, no evidence of HGT was detected in the MTBC.
Young, D. B., Comas, I. & de Carvalho, L. P. Phylogenetic analysis of vitamin B12-related metabolism in Mycobacterium tuberculosis. Front. Mol. Biosci. 2, 6 (2015).
Zumbo, A. et al. Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis. Pathog. Dis. 69, 232–239 (2013).
Boritsch, E. C. et al. pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence. Nat. Microbiol. 1, 15019 (2016).
Cadena, A. M., Fortune, S. M. & Flynn, J. L. Heterogeneity in tuberculosis. Nat. Rev. Immunol. 17, 691–702 (2017).
Brites, D. & Gagneux, S. Co-evolution of Mycobacterium tuberculosis and Homo sapiens. Immunol. Rev. 264, 6–24 (2015).
Smith, T. A comparative study of bovine tubercle bacilli and of human bacilli from sputum. J. Exp. Med. 3, 451–511 (1898).
Muller, B. et al. Zoonotic Mycobacterium bovis-induced tuberculosis in humans. Emerg. Infect. Dis. 19, 899–908 (2013).
Gormley, E. & Corner, L. A. Control strategies for wildlife tuberculosis in Ireland. Transbound Emerg. Dis. 60 (Suppl. 1), 128–135 (2013).
Smith, N. H. et al. Ecotypes of the Mycobacterium tuberculosis complex. J. Theor. Biol. 239, 220–225 (2005).
Pym, A. S., Brodin, P., Brosch, R., Huerre, M. & Cole, S. T. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol. Microbiol. 46, 709–717 (2002).
Mostowy, S., Cousins, D. & Behr, M. A. Genomic interrogation of the dassie bacillus reveals it as a unique RD1 mutant within the Mycobacterium tuberculosis complex. J. Bacteriol. 186, 104–109 (2004).
Alexander, K. A. et al. Novel Mycobacterium tuberculosis complex pathogen, M. mungi. Emerg. Infect. Dis. 16, 1296–1299 (2010).
Mahairas, G. G., Sabo, P. J., Hickey, M. J., Singh, D. C. & Stover, C. K. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J. Bacteriol. 178, 1274–1282 (1996).
Behr, M. A. Comparative genomics of mycobacteria: some answers, yet more new questions. Cold Spring Harb. Perspect. Med. 5, a021204 (2015).
Gonzalo-Asensio, J. et al. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc. Natl Acad. Sci. USA 111, 11491–11496 (2014). This is an elegant study exploring the impact of mutations in the PhoPR two-component system on the virulence and potential host tropism in the MTBC.
Whelan, A. O. et al. Revisiting host preference in the Mycobacterium tuberculosis complex: experimental infection shows M. tuberculosis H37Rv to be avirulent in cattle. PLOS One 5, e8527 (2010).
Ameni, G. et al. Transmission of Mycobacterium tuberculosis between farmers and cattle in central Ethiopia. PLOS One 8, e76891 (2013).
Manchester, K. Tuberculosis and leprosy in antiquity: an interpretation. Med. Hist. 28, 162–173 (1984).
Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).
Garnier, T. et al. The complete genome sequence of Mycobacterium bovis. Proc. Natl Acad. Sci. USA 100, 7877–7882 (2003).
Brosch, R. et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl Acad. Sci. USA 99, 3684–3689 (2002).
Mostowy, S., Cousins, D., Brinkman, J., Aranaz, A. & Behr, M. A. Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex. J. Infect. Dis. 186, 74–80 (2002).
Dippenaar, A. et al. Whole genome sequence analysis of Mycobacterium suricattae. Tuberculosis (Edinb.) 95, 682–688 (2015).
de Jong, B. C., Antonio, M. & Gagneux, S. Mycobacterium africanum — review of an important cause of human tuberculosis in West Africa. PLOS Negl. Trop. Dis. 4, e744 (2010).
Smith, N. H., Hewinson, R. G., Kremer, K., Brosch, R. & Gordon, S. V. Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis. Nat. Rev. Microbiol. 7, 537–544 (2009).
Comas, I. et al. Population genomics of Mycobacterium tuberculosis in Ethiopia contradicts the virgin soil hypothesis for human tuberculosis in sub-Saharan Africa. Curr. Biol. 25, 3260–3266 (2015).
Comas, I. et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat. Genet. 45, 1176–1182 (2013).
Kay, G. L. et al. Eighteenth-century genomes show that mixed infections were common at time of peak tuberculosis in Europe. Nat. Commun. 6, 6717 (2015).
Bos, K. I. et al. Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis. Nature 514, 494–497 (2014).
Baker, O. et al. Human tuberculosis predates domestication in ancient Syria. Tuberculosis (Edinb.) 95 (Suppl. 1), S4–S12 (2015).
Hershkovitz, I. et al. Detection and molecular characterization of 9000-year-old Mycobacterium tuberculosis from a neolithic settlement in the Eastern Mediterranean. PLOS ONE 3, e3426 (2008).
Lee, O. Y. et al. Mycobacterium tuberculosis complex lipid virulence factors preserved in the 17,000-year-old skeleton of an extinct bison, Bison antiquus. PLOS One 7, e41923 (2012).
Eldholm, V. et al. Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 113, 13881–13886 (2016).
Ho, S. Y. & Larson, G. Molecular clocks: when times are a-changin'. Trends Genet. 22, 79–83 (2006).
Duchene, S. et al. Genome-scale rates of evolutionary change in bacteria. Microb. Genom. 2, e000094 (2016).
Comas, I. & Gagneux, S. A role for systems epidemiology in tuberculosis research. Trends Microbiol. 19, 492–500 (2011).
Gagneux, S. Host–pathogen coevolution in human tuberculosis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 850–859 (2012).
Kawecki, T. J. & Ebert, D. Conceptual issues in local adaptation. Ecol. Lett. 7, 1225–1241 (2004).
Hirsh, A. E., Tsolaki, A. G., DeRiemer, K., Feldman, M. W. & Small, P. M. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc. Natl Acad. Sci. USA 101, 4871–4876 (2004).
Baker, L., Brown, T., Maiden, M. C. & Drobniewski, F. Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerg. Infect. Dis. 10, 1568–1577 (2004).
Reed, M. B. et al. Major Mycobacterium tuberculosis lineages associate with patient country of origin. J. Clin. Microbiol. 47, 1119–1128 (2009).
Gagneux, S. et al. Variable host–pathogen compatibility in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 103, 2869–2873 (2006).
Fenner, L. et al. HIV infection disrupts the sympatric host–pathogen relationship in human tuberculosis. PLOS Genet. 9, e1003318 (2013).
Asante-Poku, A. et al. Mycobacterium africanum is associated with patient ethnicity in Ghana. PLOS Negl. Trop. Dis. 9, e3370 (2015).
Asante-Poku, A. et al. Molecular epidemiology of Mycobacterium africanum in Ghana. BMC Infect. Dis. 16, 385 (2016).
Futuyma, D. J. & Moreno, G. The evolution of ecological specialization. Annu. Rev. Ecol. Systemat. 19, 207–233 (1988).
Coll, F. et al. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains. Nat. Commun. 5, 4812 (2014).
Stucki, D. et al. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nat. Genet. 48, 1535–1543 (2016). In this study, several thousand MTBC L4 clinical isolates are subtyped into sublineages. The geographical distribution of these sublineages supports a classification into ecological specialists and generalists.
Comas, I. et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat. Genet. 42, 498–503 (2010).
Pepperell, C. S. et al. The role of selection in shaping diversity of natural M. tuberculosis populations. PLOS Pathog. 9, e1003543 (2013).
Coscolla, M. et al. M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens. Cell Host Microbe 18, 538–548 (2015).
Yruela, I., Contreras-Moreira, B., Magalhaes, C., Osorio, N. S. & Gonzalo-Asensio, J. Mycobacterium tuberculosis complex exhibits lineage-specific variations affecting protein ductility and epitope recognition. Genome Biol. Evol. 8, 3751–3764 (2016).
Blaser, M. J. & Kirschner, D. The equilibria that allow bacterial persistence in human hosts. Nature 449, 843–849 (2007).
Zheng, N., Whalen, C. C. & Handel, A. Modeling the potential impact of host population survival on the evolution of M. tuberculosis latency. PLOS One 9, e105721 (2014).
Barnes, I., Duda, A., Pybus, O. G. & Thomas, M. G. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution 65, 842–848 (2011).
Coscolla, M. & Gagneux, S. Does M. tuberculosis genomic diversity explain disease diversity? Drug Discov. Today Dis. Mech. 7, e43–e59 (2010).
Hershberg, R. et al. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLOS Biol. 6, e311 (2008).
Williams, A. C. & Dunbar, R. I. Big brains, meat, tuberculosis and the nicotinamide switches: co-evolutionary relationships with modern repercussions on longevity and disease? Med. Hypotheses 83, 79–87 (2014).
Supply, P. et al. Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Mol. Microbiol. 47, 529–538 (2003).
Gagneux, S. & Small, P. M. Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development. Lancet Infect. Dis. 7, 328–337 (2007).
Comas, I., Homolka, S., Niemann, S. & Gagneux, S. Genotyping of genetically monomorphic bacteria: DNA sequencing in mycobacterium tuberculosis highlights the limitations of current methodologies. PLOS ONE 4, e7815 (2009).
Comas, I. et al. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat. Genet. 44, 106–110 (2012). In this study, the authors use a combination of experimental evolution and molecular epidemiological data to identify fitness compensatory mutations in the RNA polymerase of rifampicin-resistant MTBC.
Farhat, M. R. et al. Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis. Nat. Genet. 45, 1183–1189 (2013).
Namouchi, A., Didelot, X., Schock, U., Gicquel, B. & Rocha, E. P. After the bottleneck: genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res. 22, 721–734 (2012).
Liu, X., Gutacker, M. M., Musser, J. M. & Fu, Y. X. Evidence for recombination in Mycobacterium tuberculosis. J. Bacteriol. 188, 8169–8177 (2006).
Smith, N. H., Gordon, S. V., de la Rua-Domenech, R., Clifton-Hadley, R. S. & Hewinson, R. G. Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis. Nat. Rev. Microbiol. 4, 670–681 (2006).
Maynard Smith, J. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23–35 (1974).
Eldholm, V. et al. Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient. Genome Biol. 15, 490 (2014).
Charlesworth, B. Background selection 20 years on: the Wilhelmine, E. Key 2012 invitational lecture. J. Hered. 104, 161–171 (2013).
Pepperell, C. et al. Bacterial genetic signatures of human social phenomena among M. tuberculosis from an Aboriginal Canadian population. Mol. Biol. Evol. 27, 427–440 (2010).
Trauner, A. et al. The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy. Genome Biol. 18, 71 (2017).
Keinan, A. & Clark, A. G. Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336, 740–743 (2012).
Luo, T. et al. Southern East Asian origin and coexpansion of Mycobacterium tuberculosis Beijing family with Han Chinese. Proc. Natl Acad. Sci. USA 112, 8136–8141 (2015).
Merker, M. et al. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat. Genet. 47, 242–249 (2015).
Lieberman, T. D. et al. Genomic diversity in autopsy samples reveals within-host dissemination of HIV-associated Mycobacterium tuberculosis. Nat. Med. 22, 1470–1474 (2016). This paper provides a detailed view into the within-host diversity and evolution of the MTBC, using thousands of genome sequences obtained from individuals co-infected with HIV and TB who died before treatment initiation.
Dean, G. S. et al. Minimum infective dose of Mycobacterium bovis in cattle. Infect. Immun. 73, 6467–6471 (2005).
Charlesworth, B. Fundamental concepts in genetics: effective population size and patterns of molecular evolution and variation. Nat. Rev. Genet. 10, 195–205 (2009).
Eldholm, V. & Balloux, F. Antimicrobial resistance in Mycobacterium tuberculosis: the odd one out. Trends Microbiol. 24, 637–648 (2016).
Bloemberg, G. V. et al. Acquired resistance to bedaquiline and delamanid in therapy for tuberculosis. N. Engl. J. Med. 373, 1986–1988 (2015). This is the first report of the acquisition of resistance to the two new tuberculosis drugs bedaquiline and delamanid during the treatment of a single patient.
Gygli, S. M., Borrell, S., Trauner, A. & Gagneux, S. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiol. Rev. 41, 354–373 (2017).
Muller, B., Borrell, S., Rose, G. & Gagneux, S. The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis. Trends Genet. 29, 160–169 (2013).
Middlebrook, G. & Cohn, M. L. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science 118, 297–299 (1953).
Manson, A. L. et al. Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. Nat. Genet. 49, 395–402 (2017). This study is the largest whole-genome-based analysis of MTBC drug resistance to date.
Sander, P. et al. Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob. Agents Chemother. 46, 1204–1211 (2002).
Gagneux, S. et al. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312, 1944–1946 (2006).
Sherman, D. R. et al. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272, 1641–1643 (1996).
Song, T. et al. Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β' subunit of RNA polymerase. Mol. Microbiol. 91, 1106–1119 (2014).
de Vos, M. et al. Putative compensatory mutations in the rpoC gene of rifampin-resistant Mycobacterium tuberculosis are associated with ongoing transmission. Antimicrob. Agents Chemother. 57, 827–832 (2013).
Borrell, S. et al. Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis. Evol. Med. Public Health 2013, 65–74 (2013).
Fenner, L. et al. Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 3047–3053 (2012).
Borrell, S. & Gagneux, S. Infectiousness, reproductive fitness and evolution of drug-resistant Mycobacterium tuberculosis. Int. J. Tuberc Lung Dis. 13, 1456–1466 (2009).
Werngren, J. & Hoffner, S. E. Drug-susceptible Mycobacterium tuberculosis Beijing genotype does not develop mutation-conferred resistance to rifampin at an elevated rate. J. Clin. Microbiol. 41, 1520–1524 (2003).
Ford, C. B. et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat. Genet. 45, 784–790 (2013).
Copin, R. et al. Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition. mBio 5, e00960–e00913 (2014).
Kwan, C. K. & Ernst, J. D. HIV and tuberculosis: a deadly human syndemic. Clin. Microbiol. Rev. 24, 351–376 (2011).
Rappuoli, R., Bottomley, M. J., D'Oro, U., Finco, O. & De Gregorio E. Reverse vaccinology 2.0: human immunology instructs vaccine antigen design. J. Exp. Med. 213, 469–481 (2016).
Tameris, M. D. et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381, 1021–1028 (2013).
Eldholm, V. et al. Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis. eLife 213, 469–481 (2016).
Koch, A. S. et al. The influence of HIV on the evolution of Mycobacterium tuberculosis. Mol. Biol. Evol. 34, 1654–1668 (2017).
Copin, R. et al. Within host evolution selects for a dominant genotype of Mycobacterium tuberculosis while T cells increase pathogen genetic diversity. PLOS Pathog. 12, e1006111 (2016).
Brites, D. & Gagneux, S. The nature and evolution of genomic diversity in the Mycobacterium tuberculosis complex. Adv. Exp. Med. Biol. 1019, 1–26 (2017).
Casali, N. et al. Evolution and transmission of drug-resistant tuberculosis in a Russian population. Nat. Genet. 46, 279–286 (2014).
The author thanks all the members of his group for the stimulating discussions over the years. Work in the author's laboratory is supported by the Swiss National Science Foundation (grants 310030_166687, IZRJZ3_164171 and IZLSZ3_170834), the European Research Council (309540-EVODRTB) and SystemsX.ch.
The author declares no competing financial interests.
- Acid-fast bacilli
Mycobacteria that have a thick, lipid-rich cell wall that retains staining despite acid treatment; hence 'acid-fast'.
- Multilocus sequence typing
A standard genotyping method based on sequence data from approximately seven housekeeping genes, which together define strain-specific sequence types.
- Professional pathogen
A pathogen with no environmental reservoir that has to cause disease to transmit from host to host.
Mycobacteria that form colonies in less than 7 days.
Mycobacteria that form colonies in more than 7 days.
- PhoPR two-component system
Mycobacterial transcription factors involved in Mycobacterium tuberculosis complex virulence.
- DosR/S/T regulon
A set of mycobacterial genes involved in latent tuberculosis infection.
- mce-associated genes
Mycobacterial genes originally identified as being involved in macrophage entry.
- ESAT6 secretion
(ESX). A protein secretion apparatus that, in the case of the Mycobacterium tuberculosis complex, exports many virulence determinants.
- Toxin–antitoxin system genes
Regulatory systems comprised of two linked genes, one encoding the toxin and the other encoding the neutralizing antitoxin.
- Smooth tubercle bacilli
(STB). Organisms that produce smooth colonies on agar plates, which is in contrast to the Mycobacterium tuberculosis complex, which produces rough colonies.
- Distributive conjugal transfer
A phage-dependent mechanism of DNA transfer between bacteria.
Bacterial variants that have incorporated DNA from other bacteria through conjugation.
- Spillover events
The occasional transfer of a particular Mycobacterium tuberculosis complex variant from its primary host species into another host species.
An alternative classification of bacterial genotypes that incorporates ecological characteristics.
Host and pathogen variants that co-occur in a given geographical setting.
Host and pathogen variants that usually occur in geographically separate settings.
- T cell epitopes
Parts of the Mycobacterium tuberculosis complex proteome (that is, peptides) that are recognized by T lymphocytes.
- Founder effects
The random introduction of a particular bacterial variant into a given setting.
Characters acquired independently by two or more bacterial variants that do not share an immediate common ancestor.
- Selective sweeps
Positive selection that leads to the fixation of a new beneficial mutation.
- Background selection
Selection against a deleterious mutation that leads to the elimination of any mutation linked to the target of selection.
- Purifying selection
Selection against detrimental mutations.
- Transmission bottlenecks
A type of population bottleneck in which only a subset of the bacterial diversity present in one host is transmitted to the next.
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Gagneux, S. Ecology and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol 16, 202–213 (2018). https://doi.org/10.1038/nrmicro.2018.8
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