Compensatory evolution drives multidrug-resistant tuberculosis in central Asia

Matthias Merker; Maxime Barbier; Helen Cox; Jean Philippe Rasigade; Silke Feuerriegel; Thomas Andreas Kohl; Roland Diel; Sonia Borrell; Sebastien Gagneux; Vladyslav Nikolayevskyy; Sönke Andres; Ulrich Nübel; Philip Supply; Thierry Wirth; Stefan Niemann

doi:10.7554/eLife.38200

Compensatory evolution drives multidrug-resistant tuberculosis in central Asia

Matthias Merker^*, Maxime Barbier, Helen Cox, Jean Philippe Rasigade, Silke Feuerriegel, Thomas Andreas Kohl, Roland Diel, Sonia Borrell, Sebastien Gagneux, Vladyslav Nikolayevskyy, Sönke Andres, Ulrich Nübel, Philip Supply, Thierry Wirth, Stefan Niemann

^*Corresponding author for this work

Clinic of Internal Medicine III - Pulmonology

112 Citations (Scopus)

Abstract

Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001–2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969–1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008– 2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

Original language	English
Article number	e38200
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.38200
Publication status	Published - 10.2018

Funding

We thank: I Razio, P Vock, T Ubben and J Zallet from Borstel, Germany for technical assistance; the national and expatriate staff of Médecins Sans Frontières, Karakalpakstan; Dr. Atadjan and Dr. K Khamraev from the Ministry of Health (Karakalpakstan) for their support. Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project and the German Center for Infection Research and by the Leibniz Science Campus Evolutionary Medicine of the Lung (Evo-Lung). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Raw sequence data (fastq files) have been deposited at the European Nucleotide Archive (ENA) under the project number ERP000192.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.38200

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@article{d5f43ed205794255a287e2fc8c4331fe,

title = "Compensatory evolution drives multidrug-resistant tuberculosis in central Asia",

abstract = "Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001–2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95\% HPD 1969–1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75\% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008– 2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.",

author = "Matthias Merker and Maxime Barbier and Helen Cox and Rasigade, \{Jean Philippe\} and Silke Feuerriegel and Kohl, \{Thomas Andreas\} and Roland Diel and Sonia Borrell and Sebastien Gagneux and Vladyslav Nikolayevskyy and S{\"o}nke Andres and Ulrich N{\"u}bel and Philip Supply and Thierry Wirth and Stefan Niemann",

note = "Funding Information: We thank: I Razio, P Vock, T Ubben and J Zallet from Borstel, Germany for technical assistance; the national and expatriate staff of M{\'e}decins Sans Fronti{\`e}res, Karakalpakstan; Dr. Atadjan and Dr. K Khamraev from the Ministry of Health (Karakalpakstan) for their support. Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project and the German Center for Infection Research and by the Leibniz Science Campus Evolutionary Medicine of the Lung (Evo-Lung). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Raw sequence data (fastq files) have been deposited at the European Nucleotide Archive (ENA) under the project number ERP000192. Publisher Copyright: {\textcopyright} Merker et al. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

month = oct,

doi = "10.7554/eLife.38200",

language = "English",

volume = "7",

journal = "eLife",

issn = "2050-084X",

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T1 - Compensatory evolution drives multidrug-resistant tuberculosis in central Asia

AU - Merker, Matthias

AU - Barbier, Maxime

AU - Cox, Helen

AU - Rasigade, Jean Philippe

AU - Feuerriegel, Silke

AU - Kohl, Thomas Andreas

AU - Diel, Roland

AU - Borrell, Sonia

AU - Gagneux, Sebastien

AU - Nikolayevskyy, Vladyslav

AU - Andres, Sönke

AU - Nübel, Ulrich

AU - Supply, Philip

AU - Wirth, Thierry

AU - Niemann, Stefan

N1 - Funding Information: We thank: I Razio, P Vock, T Ubben and J Zallet from Borstel, Germany for technical assistance; the national and expatriate staff of Médecins Sans Frontières, Karakalpakstan; Dr. Atadjan and Dr. K Khamraev from the Ministry of Health (Karakalpakstan) for their support. Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project and the German Center for Infection Research and by the Leibniz Science Campus Evolutionary Medicine of the Lung (Evo-Lung). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Raw sequence data (fastq files) have been deposited at the European Nucleotide Archive (ENA) under the project number ERP000192. Publisher Copyright: © Merker et al. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/10

Y1 - 2018/10

N2 - Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001–2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969–1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008– 2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

AB - Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001–2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969–1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008– 2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

UR - https://www.scopus.com/pages/publications/85055617032

U2 - 10.7554/eLife.38200

DO - 10.7554/eLife.38200

M3 - Journal articles

C2 - 30373719

AN - SCOPUS:85055617032

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e38200

ER -

Compensatory evolution drives multidrug-resistant tuberculosis in central Asia

Abstract

Funding

Research Areas and Centers

UN SDGs

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