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Abstract：
BACKGROUND: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.
METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.
RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).
CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.
METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.
RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).
CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.
摘要：
背景：鸟分枝杆菌复合物（MAC）包括中欧最常见的非结核分枝杆菌（NTM），目前包括12种。M.avium（MAV），M.细胞内亚种。细胞内（MINT），和M.胞内亚种。嵌合体（MCH）是临床上最相关的。然而,与潜在病理生物学差异相关的MAC的种群结构和基因组景观仍然很少研究。
方法：对来自德国的多国MAC分离株进行全基因组测序（WGS），法国,和瑞士。进行了系统发育分析，以及质粒，阻力,和从WGS数据预测的毒力基因。将数据设置为具有公开可用序列的全球背景。最后,详细的临床特征与部分队列的基因组数据相关.
结果：总体而言，纳入了来自465名患者的610个分离株。多数可以分配给MAV(n=386)，MCH（n=111），和MINT（n=77）。我们证明了从所有主要MAC物种中的不同患者获得的分离株的距离小于12个SNP的聚类，以及与1307个公共序列相关时跨欧洲甚至跨大陆簇的鉴定。然而,我们的MCH隔离物没有一个与加热器-冷却器单元爆发菌株Zuerich-1紧密聚集。在MAV中检测到已知的质粒（325/1076，30.2％），MINT（62/327，19.0%），和几乎所有的MCH分离株（457/463，98.7%）。对氨基糖苷类或大环内酯类的预期耐药性很少。总的来说,系统基因组分组和临床表现之间没有直接联系，但是在肺外疾病患者中很少发现MCH和MINT（分别为OR0.1295％CI0.04-0.28，p<0.001和OR0.1195％CI0.02-0.4，p=0.004），并且MCH与从呼吸道样本中分离时的ATS标准的满足呈负相关（OR0.2895％CI0.09-0.7，p=0.011）。43名患者中有14名获得了系列分离株，与MAC的不同菌株甚至物种的共感染或共定殖是常见的（32.6％）。
结论：这项研究表明，在欧洲和全球范围内，大部分MAC分离株中存在质粒。未来的研究需要紧急定义MAC分离株的潜在传播方式以及质粒在毒力中的潜在参与。
方法：对来自德国的多国MAC分离株进行全基因组测序（WGS），法国,和瑞士。进行了系统发育分析，以及质粒，阻力,和从WGS数据预测的毒力基因。将数据设置为具有公开可用序列的全球背景。最后,详细的临床特征与部分队列的基因组数据相关.
结果：总体而言，纳入了来自465名患者的610个分离株。多数可以分配给MAV(n=386)，MCH（n=111），和MINT（n=77）。我们证明了从所有主要MAC物种中的不同患者获得的分离株的距离小于12个SNP的聚类，以及与1307个公共序列相关时跨欧洲甚至跨大陆簇的鉴定。然而,我们的MCH隔离物没有一个与加热器-冷却器单元爆发菌株Zuerich-1紧密聚集。在MAV中检测到已知的质粒（325/1076，30.2％），MINT（62/327，19.0%），和几乎所有的MCH分离株（457/463，98.7%）。对氨基糖苷类或大环内酯类的预期耐药性很少。总的来说,系统基因组分组和临床表现之间没有直接联系，但是在肺外疾病患者中很少发现MCH和MINT（分别为OR0.1295％CI0.04-0.28，p<0.001和OR0.1195％CI0.02-0.4，p=0.004），并且MCH与从呼吸道样本中分离时的ATS标准的满足呈负相关（OR0.2895％CI0.09-0.7，p=0.011）。43名患者中有14名获得了系列分离株，与MAC的不同菌株甚至物种的共感染或共定殖是常见的（32.6％）。
结论：这项研究表明，在欧洲和全球范围内，大部分MAC分离株中存在质粒。未来的研究需要紧急定义MAC分离株的潜在传播方式以及质粒在毒力中的潜在参与。
