Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis

Matthias Merker (1, 2) , Jean-Philippe Rasigade (3, 4) , Maxime Barbier (3) , Helen Cox (5) , Silke Feuerriegel (1, 2) , Thomas A Kohl (1, 2) , Egor Shitikov (6) , Kadri Klaos , Cyril Gaudin (7) , Rudy Antoine (8, 9) , Roland Diel (10, 11) , Sonia Borrell (12, 13) , Sebastien Gagneux (12, 13) , Vladyslav Nikolayevskyy (14) , Sönke Andres (1) , Valeriu Crudu , Philip Supply (8, 9) , Stefan Niemann (1, 2) , Thierry Wirth (3)

1 Forschungszentrum Borstel - Research Center Borstel
2 German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems
3 ISYEB - Institut de Systématique, Evolution, Biodiversité
4 CIRI - Centre International de Recherche en Infectiologie
5 University of Cape Town
6 Clinical Centre of Physical-Chemical Medicine [Moscow]
7 Genoscreen [Lille]
8 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
9 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
10 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
11 German Center for Lung Research
12 Unibas - Université de Bâle = University of Basel = Basel Universität
13 Swiss Tropical and Public Health Institute [Basel]
14 Imperial College London

Abstract Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.

Domaines: Bactériologie; Génétique des populations [q-bio.PE]; Maladies infectieuses

Matthias Merker, Jean-Philippe Rasigade, Maxime Barbier, Helen Cox, Silke Feuerriegel, et al.. Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis. Nature Communications, 2022, 13 (1), pp.5105. ⟨10.1038/s41467-022-32455-1⟩. ⟨hal-03837079⟩