Introduction

TB in humans and animals is caused by a group of acid-fast bacteria collectively known as the Mycobacterium tuberculosis Complex (MTBC). The MTBC consists in a clonal group of highly related mycobacterial lineages (99.9% nucleotide identity, 2,500 SNPs maximum) pathogenic to a range of different mammalian hosts. The identifications of specific characteristics of strains within a species have allowed to identify outbreaks [1,2] The MTBC comprises of the obligate human pathogens Mycobacterium tuberculosis sensu stricto and Mycobacterium africanum, several lineages mainly affecting wild and domestic mammalian hosts, and the so-called “smooth tubercle bacilli” that include Mycobacterium canettii. A clonal population arose, apparently, from one of the M. canettii-like ancestors and became the MTBC with very little diversity but a large geographic and host species variation. Identifying the adaptive traits of human-adapted MTBC and unravelling the bacterial loci that interact with human genomic variation might help identify new targets for developing better vaccines and designing more effective treatments.

[1] Bifani PJ. Identification of a W Variant Outbreak of Mycobacterium tuberculosis via Population-Based Molecular Epidemiology. JAMA 1999;282:2321. doi:10.1001/jama.282.24.2321.

[2] Long R, Nobert E, Chomyc S, van EMBDEN J, McNAMEE C, Duran RR, et al. Transcontinental Spread of Multidrug-resistant Mycobacterium bovis. Am J Respir Crit Care Med 1999;159:2014–7. doi:10.1164/ajrccm.159.6.9809076.

MTBC evolution

The evolution of tuberculosis-causing mycobacteria started from a common ancestor of M. tuberculosis and M. canettii. During recent evolution, M. tuberculosis has lost the ability to produce lipo-oligosaccharides and for inter-strain transfer of DNA. It has a clonal population structure. Genetic deletion analyses established the first evolutionary scheme of tuberculosis-causing Mycobacteria (Brosch PNAS 2002)[2].

The evolution of this lineage which is now called Mycobacterium tuberculosis complex (MTBC) is going on through SNPs, insertions or deletions leading to different human and animal lineages. Animal lineages of MTBC originate from M. africanum-like lineages. Genetic exchanges of small DNA fragments between M. tuberculosis complex strains have been described [1].

Emerging high-throughput technologies, in particular Next-Generation Sequencing (NGS) offer new opportunities, and have already lead to important new insights. NGS confirmed the scheme identified by deletion analyses (see next bloc).

[1] Namouchi A, Didelot X, Schock U, Gicquel B, Rocha EPC. After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res 2012;22:721–34. doi:10.1101/gr.129544.111.

[2] Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci 2002;99:3684–9. doi:10.1073/pnas.052548299.

Phylogeny Tree

The seven human-adapted lineages comprise of M. tuberculosis sensu stricto Lineages 1–4, Lineage 7, as well as M. africanum Lineages 5 and 6. Lineage 1, ancestor Mycobacterium tuberculosis (Mtb) strain, (also known as Indo- Oceanic or EAI). The modern TbD1 deleted TB strains which are lineage 2 (East-Asian lineage; includes the Beijing family of strains), lineage 3 (Central Asian Strain, CAS) and lineage 4 (Euro-American lineage). Lineage 5 (M. africanum West Africa 1) and Lineage 6 (M. africanum West Africa 2) with the RD9 deletion. Lineage 7 was recently identified. M. canettii is the outgroup. There is experimental evidence of transfer of multiple, large chromosomal fragments between two M. canettii strains [1]. Animal lineage 8 (M. microti, M. pinnipedii, M. orygis, M. caprae, M. bovis) was branching from RD9-deleted M. africanum. See below the Phylogenetic tree of MTBC bacteria with data from Takiff [2] Comas [3] Blouin [4] Brites and Gagneux p1-26 in [5] and Boritsch [6]

[1] Boritsch EC, Khanna V, Pawlik A, Honoré N, Navas VH, Ma L, et al. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc Natl Acad Sci 2016;113:9876–81. doi:10.1073/pnas.1604921113.

[2] Takiff HE, Feo O. Clinical value of whole-genome sequencing of Mycobacterium tuberculosis. Lancet Infect Dis 2015;15:1077–90. doi:10.1016/S1473-3099(15)00071-7.

[3] Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 2013;45:1176–82. doi:10.1038/ng.2744.

[4] Blouin Y, Hauck Y, Soler C, Fabre M, Vong R, Dehan C, et al. Significance of the Identification in the Horn of Africa of an Exceptionally Deep Branching Mycobacterium tuberculosis Clade. PLoS ONE 2012;7:e52841. doi:10.1371/journal.pone.0052841.

[5] Gagneux S. Strain variation in the mycobacterium tuberculosis complex: its role in biology, epidemiology and control. New York, NY: Springer Berlin Heidelberg; 2017.

[6] Boritsch EC, Supply P, Honoré N, Seeman T, Stinear TP, Brosch R. A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent: Molecular evolution. Mol Microbiol 2014;93:835–52. doi:10.1111/mmi.12720.

Distribution of MTBC lineages

The geographical spread of the seven human-adapted lineages differs markedly, with some lineages exhibiting a global distribution and others a strong geographical restriction [1,2]. Lineage 2 (East-Asian lineage including the Beijing family) and Lineage 4 (Euro-American lineage) occur worldwide. M. africanum Lineages 5 and 6 are highly restricted to West-Africa [3], while Lineage 7 occurs almost exclusively in Ethiopia [4]. The remaining two lineages show an intermediate distribution, with Lineage 1 (also known as Indo-Oceanic or EAI) occurring all around the Indian Ocean and Lineage 3 (CAS) dominating in parts of East Africa, Central and South-Asia [5].

Bibliographie

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[1] Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci 2006;103:2869–73. doi:10.1073/pnas.0511240103.

[2] Gagneux S, Small PM. Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development. Lancet Infect Dis 2007;7:328–37. doi:10.1016/S1473-3099(07)70108-1.

[3] de Jong BC, Antonio M, Gagneux S. Mycobacterium africanum—Review of an Important Cause of Human Tuberculosis in West Africa. PLoS Negl Trop Dis 2010;4:e744. doi:10.1371/journal.pntd.0000744.

[4] Firdessa R, Berg S, Hailu E, Schelling E, Gumi B, Erenso G, et al. Mycobacterial Lineages Causing Pulmonary and Extrapulmonary Tuberculosis, Ethiopia. Emerg Infect Dis 2013;19:460–3. doi:10.3201/eid1903.120256.

[5] Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka S, et al. High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography. PLoS Biol 2008;6:e311. doi:10.1371/journal.pbio.0060311.

[6] Gagneux S. Strain variation in the mycobacterium tuberculosis complex: its role in biology, epidemiology and control. New York, NY: Springer Berlin Heidelberg; 2017.

[7] Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 2013;45:1176–82. doi:10.1038/ng.2744.