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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients
PLoS ONE, Volume 8, No. 12, Article e82551, Year 2013
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Description
Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains represent a major threat for tuberculosis (TB) control. Treatment of MDR-TB patients is long and less effective, resulting in a significant number of treatment failures. The development of further resistances leads to extensively drug-resistant (XDR) variants. However, data on the individual reasons for treatment failure, e.g. an induced mutational burst, and on the evolution of bacteria in the patient are only sparsely available. To address this question, we investigated the intra-patient evolution of serial MTBC isolates obtained from three MDR-TB patients undergoing longitudinal treatment, finally leading to XDR-TB. Sequential isolates displayed identical IS6110 fingerprint patterns, suggesting the absence of exogenous re-infection. We utilized whole genome sequencing (WGS) to screen for variations in three isolates from Patient A and four isolates from Patient B and C, respectively. Acquired polymorphisms were subsequently validated in up to 15 serial isolates by Sanger sequencing. We determined eight (Patient A) and nine (Patient B) polymorphisms, which occurred in a stepwise manner during the course of the therapy and were linked to resistance or a potential compensatory mechanism. For both patients, our analysis revealed the long-term co-existence of clonal subpopulations that displayed different drug resistance allele combinations. Out of these, the most resistant clone was fixed in the population. In contrast, baseline and follow-up isolates of Patient C were distinguished each by eleven unique polymorphisms, indicating an exogenous re-infection with an XDR strain not detected by IS6110 RFLP typing. Our study demonstrates that intra-patient microevolution of MDR-MTBC strains under longitudinal treatment is more complex than previously anticipated. However, a mutator phenotype was not detected. The presence of different subpopulations might confound phenotypic and molecular drug resistance tests. Furthermore, high resolution WGS analysis is necessary to accurately detect exogenous re-infection as classical genotyping lacks discriminatory power in high incidence settings. © 2013 Merker et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3855793/bin/pone.0082551.s001.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC3855793/bin/pone.0082551.s002.docx
Authors & Co-Authors
Merker, Matthias
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Kohl, Thomas Andreas
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Roetzer, Andreas
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Austria, Vienna
Biomedizinische Forschungsgesellschaft Mbh
Truebe, Leona
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Richter, Elvira
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Rüsch-Gerdes, Sabine
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Fattorini, Lanfranco
Italy, Rome
Istituto Superiore Di Sanita
Oggioni, Marco R.
United Kingdom, Leicester
University of Leicester
Cox, Helen S.
Switzerland, Geneva
Medecins Sans Frontieres
South Africa, Cape Town
University of Cape Town
Varaine, Francis F.V.
Switzerland, Geneva
Medecins Sans Frontieres
Niemann, Stefan
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Statistics
Citations: 11
Authors: 11
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0082551
e-ISSN:
19326203
Research Areas
Genetics And Genomics
Health System And Policy
Infectious Diseases
Study Design
Cross Sectional Study
Cohort Study