Department of Systems Biology, Harvard Medical School, Boston, United States.
Department of Biomedical Informatics, Harvard Medical School, Boston, United States.
Elife. 2021 Feb 1;10:e61805. doi: 10.7554/eLife.61805.
Tuberculosis (TB) is a leading cause of death globally. Understanding the population dynamics of TB's causative agent complex (Mtbc) in-host is vital for understanding the efficacy of antibiotic treatment. We use longitudinally collected clinical Mtbc isolates that underwent Whole-Genome Sequencing from the sputa of 200 patients to investigate Mtbc diversity during the course of active TB disease after excluding 107 cases suspected of reinfection, mixed infection or contamination. Of the 178/200 patients with persistent clonal infection >2 months, 27 developed new resistance mutations between sampling with 20/27 occurring in patients with pre-existing resistance. Low abundance resistance variants at a purity of ≥19% in the first isolate predict fixation in the subsequent sample. We identify significant in-host variation in 27 genes, including antibiotic resistance genes, metabolic genes and genes known to modulate host innate immunity and confirm several to be under positive selection by assessing phylogenetic convergence across a genetically diverse sample of 20,352 isolates.
结核病（TB）是全球主要死因之一。了解宿主中结核分枝杆菌复合体（Mtbc）的种群动态对于理解抗生素治疗的效果至关重要。我们使用从 200 名患者的痰液中纵向收集的全基因组测序的临床 Mtbc 分离株，在排除 107 例疑似再感染、混合感染或污染的病例后，调查活动性结核病期间 Mtbc 的多样性。在 178/200 名持续克隆感染>2 个月的患者中，有 27 名在采样期间出现新的耐药突变，其中 20/27 名患者存在先前存在的耐药性。第一个分离株中纯度≥19%的低丰度耐药变体可预测后续样本中的固定。我们在 27 个基因中发现了显著的宿主内变异，包括抗生素耐药基因、代谢基因和已知调节宿主固有免疫的基因，并通过评估来自 20,352 个分离株的遗传多样化样本中的系统发育收敛性，确认其中几个基因受到正选择。
