The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy

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dc.contributor.authorTrauner, Andrej
dc.contributor.authorLiu, Qingyun
dc.contributor.authorVia, Laura E
dc.contributor.authorLiu, Xin
dc.contributor.authorRuan, Xianglin
dc.contributor.authorLiang, Lili
dc.contributor.authorShi, Huimin
dc.contributor.authorChen, Ying
dc.contributor.authorWang, Ziling
dc.contributor.authorLiang, Ruixia
dc.contributor.authorZhang, Wei
dc.contributor.authorWei, Wang
dc.contributor.authorGao, Jingcai
dc.contributor.authorSun, Gang
dc.contributor.authorBrites, Daniela
dc.contributor.authorEngland, Kathleen
dc.contributor.authorZhang, Guolong
dc.contributor.authorGagneux, Sébastien
dc.contributor.authorBarry, Clifton E
dc.contributor.authorGao, Qian
dc.date.accessioned2021-10-08T07:04:06Z
dc.date.available2021-10-08T07:04:06Z
dc.date.issued2017
dc.description.abstractBACKGROUND: Combination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics. RESULTS: By combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance. CONCLUSIONS: Our findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.
dc.identifier.apacitationTrauner, A., Liu, Q., Via, L. E., Liu, X., Ruan, X., Liang, L., ... Gao, Q. (2017). The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy. <i>Genome Biology</i>, 18(1), 174 - 177. http://hdl.handle.net/11427/34426en_ZA
dc.identifier.chicagocitationTrauner, Andrej, Qingyun Liu, Laura E Via, Xin Liu, Xianglin Ruan, Lili Liang, Huimin Shi, et al "The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy." <i>Genome Biology</i> 18, 1. (2017): 174 - 177. http://hdl.handle.net/11427/34426en_ZA
dc.identifier.citationTrauner, A., Liu, Q., Via, L.E., Liu, X., Ruan, X., Liang, L., Shi, H. & Chen, Y. et al. 2017. The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy. <i>Genome Biology.</i> 18(1):174 - 177. http://hdl.handle.net/11427/34426en_ZA
dc.identifier.issn1474-7596
dc.identifier.issn1474-760X
dc.identifier.ris TY - Journal Article AU - Trauner, Andrej AU - Liu, Qingyun AU - Via, Laura E AU - Liu, Xin AU - Ruan, Xianglin AU - Liang, Lili AU - Shi, Huimin AU - Chen, Ying AU - Wang, Ziling AU - Liang, Ruixia AU - Zhang, Wei AU - Wei, Wang AU - Gao, Jingcai AU - Sun, Gang AU - Brites, Daniela AU - England, Kathleen AU - Zhang, Guolong AU - Gagneux, Sébastien AU - Barry, Clifton E AU - Gao, Qian AB - BACKGROUND: Combination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics. RESULTS: By combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance. CONCLUSIONS: Our findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations. DA - 2017 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - Genome Biology LK - https://open.uct.ac.za PY - 2017 SM - 1474-7596 SM - 1474-760X T1 - The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy TI - The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy UR - http://hdl.handle.net/11427/34426 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34426
dc.identifier.vancouvercitationTrauner A, Liu Q, Via LE, Liu X, Ruan X, Liang L, et al. The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy. Genome Biology. 2017;18(1):174 - 177. http://hdl.handle.net/11427/34426.en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Clinical Laboratory Sciences
dc.publisher.facultyFaculty of Health Sciences
dc.sourceGenome Biology
dc.source.journalissue1
dc.source.journalvolume18
dc.source.pagination174 - 177
dc.source.urihttps://dx.doi.org/10.1186/s13059-017-1196-0
dc.subject.otherAnimal Genetics and Genomics
dc.subject.otherHuman Genetics
dc.subject.otherPlant Genetics &
dc.subject.otherGenomics
dc.subject.otherMicrobial Genetics and Genomics
dc.subject.otherBioinformatics
dc.subject.otherEvolutionary Biology
dc.subject.othergenetic stability
dc.subject.otherbacteria
dc.subject.otherdrugs
dc.subject.othercombination drug therapy
dc.subject.othertuberculosis
dc.subject.otherpatients
dc.subject.othergenetic variation
dc.subject.othermonitoring
dc.subject.otherpopulation dynamics
dc.subject.otherpathogens
dc.subject.otherMycobacterium tuberculosis
dc.subject.othersequence analysis
dc.subject.otherdrug resistance
dc.subject.otherantibiotics
dc.subject.otherhumans
dc.subject.otheralleles
dc.titleThe within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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