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

Trauner, Andrej and Liu, Qingyun and Via, Laura E. and Liu, Xin and Ruan, Xianglin and Liang, Lili and Shi, Huimin and Chen, Ying and Wang, Ziling and Liang, Ruixia and Zhang, Wei and Wei, Wang and Gao, Jingcai and Sun, Gang and Brites, Daniela and England, Kathleen and Zhang, Guolong and Gagneux, Sebastien and Barry, Clifton E. and Gao, Qian. (2017) The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy. Genome biology, 18. p. 71.

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Abstract

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.; 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.; 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Tuberculosis Research (Gagneux)
UniBasel Contributors:Brites, Daniela and Gagneux, Sebastien
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:BioMed Central
ISSN:1465-6906
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:13 Apr 2018 12:52
Deposited On:29 May 2017 13:29

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