The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy.
The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy.
复制标题
结核分枝杆菌的宿主内群体动态随治疗效果的不同而变化
DOI：
10.1186/s13059-017-1196-0
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发表时间：
2017-04-19
期刊：
影响因子：
12.3
通讯作者：
Gao Q
中科院分区：
文献类型：
--
作者：
Trauner A;Liu Q;Via LE;Liu X;Ruan X;Liang L;Shi H;Chen Y;Wang Z;Liang R;Zhang W;Wei W;Gao J;Sun G;Brites D;England K;Zhang G;Gagneux S;Barry CE 3rd;Gao Q
背景：联合治疗是限制病原体耐药性出现的最有效工具之一。尽管联合治疗在各种疾病中得到广泛采用，但耐药率继续上升，导致治疗方案失败。治疗失败的机制已经得到了很好的研究，但对成功的联合治疗的过程却知之甚少。我们解决这个问题，通过研究结核病患者接受不同组合的抗生素治疗的结核分枝杆菌的人口动态。结果：通过结合非常深的全基因组测序（~1000倍全基因组覆盖率）与连续的痰液采样，我们能够检测到短暂的遗传多样性驱动的次要等位基因，这可能是耐药菌的来源明显的连续营业额。然而，我们报告说，治疗效果有一个明确的影响，人口动态：足够的药物压力承担一个明确的签名，净化选择导致明显的遗传稳定性。相比之下，M。结核病人群受到较少的药物压力显示出明显不同的动态，包括获得额外的耐药性的情况。结核病，这是很好地适应人类宿主，净化选择限制了有效治疗的个人的耐药性的进化轨迹。尽管如此，我们也报告了微小变异的持续更替，这可能在药物压力减弱的情况下导致耐药性的出现。因此，监测细菌种群动态可以为评估新型药物组合的功效提供信息指标。
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.