Yang Chongguang, Luo Tao, Shen Xin, Wu Jie, Gan Mingyu, Xu Peng, Wu Zheyuan, Lin Senlin, Tian Jiyun, Liu Qingyun, Yuan ZhengAn, Mei Jian, DeRiemer Kathryn, Gao Qian
The 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 Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, 60 College Street, New Haven, CT, USA, 06510.
Lancet Infect Dis. 2017 Mar;17(3):275-284. doi: 10.1016/S1473-3099(16)30418-2. Epub 2016 Dec 3.
Multidrug-resistance is a substantial threat to global elimination of tuberculosis. Understanding transmission patterns is crucial for control of the disease. We used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (MDR) tuberculosis and identify potential risk factors for transmission.
We did a population-based, retrospective study of patients who tested positive for tuberculosis between Jan 1, 2009, and Dec 31, 2012, in Shanghai, China. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. We measured strain diversity within and between genomically clustered isolates. Genomic and epidemiological data were combined to construct transmission networks.
367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance.
Recent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis.
National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.
多重耐药对全球结核病消除构成重大威胁。了解传播模式对于控制该疾病至关重要。我们采用基因组学和流行病学方法评估多重耐药（MDR）结核病的近期传播情况，并确定传播的潜在风险因素。
我们对2009年1月1日至2012年12月31日期间在中国上海结核病检测呈阳性的患者进行了一项基于人群的回顾性研究。我们对分离株进行了可变数目串联重复基因分型和全基因组测序。我们测量了基因组聚集分离株内部和之间的菌株多样性。结合基因组和流行病学数据构建传播网络。
7982例结核病患者中有367例（5%）患有MDR结核病，其中324例（88%）有可用于基因组分析的分离株。324株MDR菌株中有103株（32%）属于38个基因组簇，这些簇之间的单核苷酸多态性（SNP）差异为12个或更少，表明MDR菌株近期有传播。诊断延迟或年龄超过45岁的患者近期传播风险高。235例（73%）MDR结核病患者可能发生了MDR菌株传播。传播网络分析显示，38个簇中的33个（87%）在传播过程中通过突变的出现或固定积累了额外的耐药突变。103株聚集的MDR菌株中有68株（66%）具有利福平耐药的补偿性突变。
MDR结核病菌株的近期传播以及耐药性增加推动了中国上海的MDR结核病流行。全基因组测序可以测量宿主内部和之间耐药突变的异质性，并有助于确定MDR结核病的传播模式。
国家科技重大专项、中国国家自然科学基金和美国国立卫生研究院。
