Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area.
Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area.
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DOI：
10.7554/elife.05166
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发表时间：
2015-03-03
期刊：
影响因子：
7.7
通讯作者：
Glynn JR
中科院分区：
文献类型：
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作者：
Guerra-Assunção JA;Crampin AC;Houben RM;Mzembe T;Mallard K;Coll F;Khan P;Banda L;Chiwaya A;Pereira RP;McNerney R;Fine PE;Parkhill J;Clark TG;Glynn JR
为了更好地了解影响结核病传播的因素和病原体变异的作用，我们对马拉维整个地区超过15年的确诊患者的所有可用样本进行了测序。分配结核分枝杆菌谱系并构建传播网络，允许≤10单核苷酸多态(SNP)存在差异。我们定义疾病是由于最近的感染，如果网络确定的源头在5年内，并评估导致疾病的前向传播的传播性。可获得1687例疾病发作的高质量序列(占所有培养阳性病例的72%)：66%的患者与至少一名其他患者有关。患者间突变率为0.26个SNPs/年(95%可信区间0.21~0.31)。我们显示了不同血统在因近期传播引起的疾病比例和传播率(血统-2最高，血统-1最低)方面的显著差异，这些差异不受移民、艾滋病毒状况或耐药性的影响。随着时间的推移，导致疾病的传播明显减少。DOI：http://dx.doi.org/10.7554/eLife.05166.001结核病是全球重要的公共卫生威胁，在发展中国家尤为常见。很难控制疾病的传播，因为引起疾病的细菌会在感染者咳嗽或打喷嚏时传播。感染者可能需要数年时间才会出现结核病症状，因此很难追踪疫情的源头，而感染艾滋病毒的人特别容易感染这种疾病。导致大多数肺结核病例的细菌被称为结核分枝杆菌。结核分枝杆菌有几种不同的变种或“谱系”，人们认为它们传播和致病的能力可能不同。然而，之前的研究结果并不一致，而且同一谱系内的菌株之间似乎也存在许多差异。在这项研究中，Guera-Assenção等人。使用了一种名为全基因组测序的方法，以及更传统的方法来研究马拉维结核病的传播。他们对15年来从马拉维卡隆加地区的患者那里收集的每一个可用结核分枝杆菌样本的基因组进行了测序。这产生了关于导致近1700例疾病的细菌的高质量DNA序列数据。格拉-阿森桑等人利用这些海量数据。构建的网络显示了细菌是如何在社区中传播的。这表明不同的结核分枝杆菌谱系在致病和在社区中传播的能力之间存在差异。例如，与其他血统相比，血统1在感染个体后不久就不太可能导致疾病，传播的能力也更小。数据还显示，在这15年期间，由于最近感染而导致的疾病比例大幅下降。这表明该地区的结核病和艾滋病毒控制方案取得了成功。S等人的研究结果表明，了解结核病是如何大规模传播的是可能的。下一个挑战是理解为什么这些血统导致疾病和在个体之间传播的能力不同。DOI：http://dx.doi.org/10.7554/eLife.05166.002
To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21–0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time. DOI: http://dx.doi.org/10.7554/eLife.05166.001 Tuberculosis is an important public health threat around the globe and is particularly common in developing countries. It is difficult to control the spread of the disease because the bacteria that cause it can spread when an infected individual coughs or sneezes. It may take years for an infected individual to develop symptoms of tuberculosis so it can be hard to trace the source of an outbreak, and people infected with HIV are particularly susceptible to the disease. The bacterium that causes the majority of cases of tuberculosis is called Mycobacterium tuberculosis. There are several different varieties or ‘lineages’ of M. tuberculosis, and it is thought that they may vary in their ability to spread and cause disease. However, the results of previous studies have been inconsistent and there also seems to be a lot of variation between strains within the same lineage. In this study, Guerra-Assunção et al. used an approach called whole genome sequencing alongside more traditional methods to study the spread of tuberculosis in Malawi. They sequenced the genomes of every available sample of M. tuberculosis collected from patients in the Karonga district of Malawi over a 15-year period. This produced high-quality DNA sequence data about the bacteria responsible for almost 1700 cases of disease. Using this massive amount of data, Guerra-Assunção et al. constructed networks that showed how the bacteria had spread in the community. This revealed that there were differences between the ability of the various M. tuberculosis lineages to cause disease and to spread in communities. For example, lineage 1 was less likely than the other lineages to cause disease soon after infecting an individual and was less able to spread. The data also show that the proportion of cases of disease due to recent infection declined substantially during the 15-year period. This indicates that the tuberculosis and HIV control programmes in the area have been successful. Guerra-Assunção et al.'s findings show that it is possible to understand how tuberculosis is transmitted on a large scale. The next challenge is to understand why the lineages differ in their ability to cause disease and spread between individuals. DOI: http://dx.doi.org/10.7554/eLife.05166.002