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Impact of Genetic Diversity on the Biology of Complex Strains

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  • Authors: Stefan Niemann1,2, Matthias Merker3, Thomas Kohl4, Philip Supply5
  • Editors: William R. Jacobs Jr.6, Helen McShane7, Valerie Mizrahi8, Ian M. Orme9
    Affiliations: 1: Molecular Mycobacteriology, Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, 23845 Borstel, Germany; 2: German Center for Infection Research (DZIF), partner site Borstel, 23845 Borstel, Germany; 3: Molecular Mycobacteriology, Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, 23845 Borstel, Germany; 4: Molecular Mycobacteriology, Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, 23845 Borstel, Germany; 5: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d’Infection et d’Immunité de Lille, F-59000 Lille, France; 6: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 7: University of Oxford, Oxford OX3 7DQ, United Kingdom; 8: University of Cape Town, Rondebosch 7701, South Africa; 9: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0022-2016
  • Received 18 July 2016 Accepted 01 August 2016 Published 11 November 2016
  • S. Niemann, [email protected], and P. Supply, [email protected]
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  • Abstract:

    Tuberculosis (TB) remains the most deadly bacterial infectious disease worldwide. Its treatment and control are threatened by increasing numbers of multidrug-resistant (MDR) or nearly untreatable extensively drug-resistant (XDR) strains. New concepts are therefore urgently needed to understand the factors driving the TB epidemics and the spread of different strain populations, especially in association with drug resistance. Classical genotyping and, more recently, whole-genome sequencing (WGS) revealed that the world population of tubercle bacilli is more diverse than previously thought. Several major phylogenetic lineages can be distinguished, which are associated with their sympatric host population. Distinct clonal (sub)populations can even coexist within infected patients. WGS is now used as the ultimate approach for differentiating clinical isolates and for linking phenotypic to genomic variation from lineage to strain levels. Multiple lines of evidence indicate that the genetic diversity of TB strains translates into pathobiological consequences, and key molecular mechanisms probably involved in differential pathoadaptation of some main lineages have recently been identified. Evidence also accumulates on molecular mechanisms putatively fostering the emergence and rapid expansion of particular MDR and XDR strain groups in some world regions. However, further integrative studies will be needed for complete elucidation of the mechanisms that allow the pathogen to infect its host, acquire multidrug resistance, and transmit so efficiently. Such knowledge will be key for the development of the most effective new diagnostics, drugs, and vaccination strategies.

  • Citation: Niemann S, Merker M, Kohl T, Supply P. 2016. Impact of Genetic Diversity on the Biology of Complex Strains. Microbiol Spectrum 4(6):TBTB2-0022-2016. doi:10.1128/microbiolspec.TBTB2-0022-2016.


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Tuberculosis (TB) remains the most deadly bacterial infectious disease worldwide. Its treatment and control are threatened by increasing numbers of multidrug-resistant (MDR) or nearly untreatable extensively drug-resistant (XDR) strains. New concepts are therefore urgently needed to understand the factors driving the TB epidemics and the spread of different strain populations, especially in association with drug resistance. Classical genotyping and, more recently, whole-genome sequencing (WGS) revealed that the world population of tubercle bacilli is more diverse than previously thought. Several major phylogenetic lineages can be distinguished, which are associated with their sympatric host population. Distinct clonal (sub)populations can even coexist within infected patients. WGS is now used as the ultimate approach for differentiating clinical isolates and for linking phenotypic to genomic variation from lineage to strain levels. Multiple lines of evidence indicate that the genetic diversity of TB strains translates into pathobiological consequences, and key molecular mechanisms probably involved in differential pathoadaptation of some main lineages have recently been identified. Evidence also accumulates on molecular mechanisms putatively fostering the emergence and rapid expansion of particular MDR and XDR strain groups in some world regions. However, further integrative studies will be needed for complete elucidation of the mechanisms that allow the pathogen to infect its host, acquire multidrug resistance, and transmit so efficiently. Such knowledge will be key for the development of the most effective new diagnostics, drugs, and vaccination strategies.

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Global phylogenetic structure of complex (MTBC) strains presented in a neighbor joining tree with 1,000 bootstrap replicates based on 35,577 variable sites. MTBC isolates can be classified into seven major lineages that are often composed of further geographically confined subgroups. So-called “modern” MTBC lineages (lineages 2, 3, 4) are distributed worldwide, whereas infections with “ancestral” MTBC strains are mainly restricted to western and eastern Africa. (Sequence data compiled from Comas et al. [ 31 ] and Merker et al. [ 33 ]).

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0022-2016
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Phylogenetic reconstruction of the MTBC Beijing lineage population. Midpoint-rooted maximum-likelihood tree based on 110 genomes and a total of 6,001 concatenated SNPs. Characteristic mutations differentiating modern and ancestral Beijing strain types are mapped on the tree— encoding p.Arg48Gly (branch a), encoding p.Arg37Leu (branch b), and encoding p.Gly58Arg (branch c)—as is the absence of the RD181 and RD150 regions of difference. Black squares correspond to strains with an MDR or XDR phenotype, and a number sign indicates strains lacking drug susceptibility test information. Numbers on branches correspond to bootstrap values. The tree topology remains the same when H37Rv is used as an outgroup (Merker et al. [ 33 ]).

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0022-2016
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Geographical distribution of nearly 5,000 clinical Beijing (i.e., lineage 2) isolates (data from Merker et al. [ 33 ]). Evolutionary ancestral Beijing strains are mainly dominating in East Asia, the likely origin of this MTBC lineage, whereas modern Beijing strains are globally distributed, suggesting a more virulent phenotype. In addition, the effects of globalization also shape the diversity of MTBC strains in different settings, yet with unknown consequences on host-pathogen interactions and tuberculosis progression (world map from flickr.com).

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0022-2016
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