Journal article
The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy.
- Trauner A Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4002, Basel, Switzerland.
- Liu Q Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- Via LE Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, 20892, USA.
- Liu X Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Ruan X Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Liang L Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Shi H Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Chen Y Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Wang Z Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Liang R Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Zhang W Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Wei W Henan Provincial Chest Hospital, Zhengzhou, 450003, Henan, China.
- Gao J Sino-US International Research Centers of Tuberculosis, Zhengzhou, 450003, Henan, China.
- Sun G Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- Brites D Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4002, Basel, Switzerland.
- England K Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, 20892, USA.
- Zhang G Sino-US International Research Centers of Tuberculosis, Zhengzhou, 450003, Henan, China. guolongzhang@hotmail.com.
- Gagneux S Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4002, Basel, Switzerland. sebastien.gagneux@unibas.ch.
- Barry CE Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, 20892, USA. cbarry@niaid.nih.gov.
- Gao Q Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. qgao99@yahoo.com.
- 2017-04-21
Published in:
- Genome biology. - 2017
Combination therapy
Drug resistance
Tuberculosis
Whole genome sequencing
Within-host evolution
Alleles
Antitubercular Agents
Drug Resistance, Bacterial
Drug Therapy, Combination
Genetic Variation
Genome, Bacterial
Genotype
Host-Pathogen Interactions
Humans
Markov Chains
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Polymorphism, Single Nucleotide
Selection, Genetic
Sequence Analysis, DNA
Sputum
Treatment Outcome
Tuberculosis
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13059-017-1196-0
- PMID 28424085
- Persistent URL
- https://sonar.ch/global/documents/185912
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