Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients

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dc.contributor.authorMerker, Matthiasen_ZA
dc.contributor.authorKohl, Thomas Aen_ZA
dc.contributor.authorRoetzer, Andreasen_ZA
dc.contributor.authorTruebe, Leonaen_ZA
dc.contributor.authorRichter, Elviraen_ZA
dc.contributor.authorRüsch-Gerdes, Sabineen_ZA
dc.contributor.authorFattorini, Lanfrancoen_ZA
dc.contributor.authorOggioni, Marco Ren_ZA
dc.contributor.authorCox, Helenen_ZA
dc.contributor.authorVaraine, Francisen_ZA
dc.date.accessioned2015-12-28T06:47:49Z
dc.date.available2015-12-28T06:47:49Z
dc.date.issued2013en_ZA
dc.description.abstractMultidrug-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 IS 6110 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 IS 6110 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.en_ZA
dc.identifier.apacitationMerker, M., Kohl, T. A., Roetzer, A., Truebe, L., Richter, E., Rüsch-Gerdes, S., ... Varaine, F. (2013). Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. <i>PLoS One</i>, http://hdl.handle.net/11427/16055en_ZA
dc.identifier.chicagocitationMerker, Matthias, Thomas A Kohl, Andreas Roetzer, Leona Truebe, Elvira Richter, Sabine Rüsch-Gerdes, Lanfranco Fattorini, Marco R Oggioni, Helen Cox, and Francis Varaine "Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16055en_ZA
dc.identifier.citationMerker, M., Kohl, T. A., Roetzer, A., Truebe, L., Richter, E., Rüsch-Gerdes, S., ... & Niemann, S. (2012). Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. PloS one, 8(12), e82551. doi:10.1371/journal.pone.0082551en_ZA
dc.identifier.ris TY - Journal Article AU - Merker, Matthias AU - Kohl, Thomas A AU - Roetzer, Andreas AU - Truebe, Leona AU - Richter, Elvira AU - Rüsch-Gerdes, Sabine AU - Fattorini, Lanfranco AU - Oggioni, Marco R AU - Cox, Helen AU - Varaine, Francis AB - 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 IS 6110 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 IS 6110 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. DA - 2013 DB - OpenUCT DO - 10.1371/journal.pone.0082551 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients TI - Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients UR - http://hdl.handle.net/11427/16055 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16055
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0082551
dc.identifier.vancouvercitationMerker M, Kohl TA, Roetzer A, Truebe L, Richter E, Rüsch-Gerdes S, et al. Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. PLoS One. 2013; http://hdl.handle.net/11427/16055.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the <a href=en_ZA
dc.rights.holder© 2013 Merker et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherFrameshift mutationen_ZA
dc.subject.otherMutationen_ZA
dc.subject.otherCloningen_ZA
dc.subject.otherMulti-drug-resistant tuberculosisen_ZA
dc.subject.otherDrug therapyen_ZA
dc.subject.otherExtensively drug-resistant tuberculosisen_ZA
dc.subject.otherMycobacterium tuberculosisen_ZA
dc.subject.otherGenome evolutionen_ZA
dc.titleWhole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patientsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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