Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia.
Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia.
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DOI：
10.1186/s13073-018-0574-x
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发表时间：
2018-08-23
期刊：
影响因子：
12.3
通讯作者：
Howden BP
中科院分区：
文献类型：
--
作者：
Giulieri SG;Baines SL;Guerillot R;Seemann T;Gonçalves da Silva A;Schultz M;Massey RC;Holmes NE;Stinear TP;Howden BP
需要对金黄色葡萄球菌菌血症 (SAB) 宿主内多样性进行大规模基因组研究，以了解持久性背后的细菌适应，从而完善基因组学在 SAB 管理中的作用。然而，现有的连续 SAB 分离株的比较基因组研究往往集中于异常长期菌血症的特定病例，这些病例已产生继发性抗菌药物耐药性。为了更广泛地了解 SAB 期间的细菌遗传多样性，我们对从持续性或复发性菌血症患者获得的大量连续分离株进行了全基因组测序。在排除遗传无关的分离株后，我们对单个 SAB 事件中出现的点突变和染色体结构变异进行了深入的基因组分析。我们发现，虽然适应途径是异质的且具有特定性，但持续性菌血症的分离株具有独特的分子特征，其特征是突变频率低和非沉默突变比例高。对结构基因组变异的分析表明，这些经常被忽视的遗传事件通常是在 SAB 期间获得的。我们发现 IS256 插入可能代表了选定谱系中宿主内微进化的最有效驱动因素，即使在没有其他突变的情况下，每个分离株也有多达三个新的插入事件。导致显着表型变化（例如万古霉素耐药性增加、小集落表型发展以及细胞毒性降低）的遗传机制包括关键基因（rpoB、stp、agrA）的突变和 walKR 操纵子上游的 IS256 插入。这项研究首次对侵入性金黄色葡萄球菌感染期间宿主内基因组变化进行了大规模分析，并描述了特定的适应模式，这将为理解金黄色葡萄球菌路径适应和利用基因组学管理复杂的金黄色葡萄球菌感染提供信息。本文的在线版本 (10.1186/s13073-018-0574-x) 包含补充材料，可供授权用户使用。
Large-scale genomic studies of within-host diversity in Staphylococcus aureus bacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in management of SAB. However, available comparative genomic studies of sequential SAB isolates have tended to focus on selected cases of unusually prolonged bacteraemia, where secondary antimicrobial resistance has developed. To understand bacterial genetic diversity during SAB more broadly, we applied whole genome sequencing to a large collection of sequential isolates obtained from patients with persistent or relapsing bacteraemia. After excluding genetically unrelated isolates, we performed an in-depth genomic analysis of point mutations and chromosome structural variants arising within individual SAB episodes. We show that, while adaptation pathways are heterogenous and episode-specific, isolates from persistent bacteraemia have a distinctive molecular signature, characterised by a low mutation frequency and high proportion of non-silent mutations. Analysis of structural genomic variants revealed that these often overlooked genetic events are commonly acquired during SAB. We discovered that IS256 insertion may represent the most effective driver of within-host microevolution in selected lineages, with up to three new insertion events per isolate even in the absence of other mutations. Genetic mechanisms resulting in significant phenotypic changes, such as increases in vancomycin resistance, development of small colony phenotypes, and decreases in cytotoxicity, included mutations in key genes (rpoB, stp, agrA) and an IS256 insertion upstream of the walKR operon. This study provides for the first time a large-scale analysis of within-host genomic changes during invasive S. aureus infection and describes specific patterns of adaptation that will be informative for both understanding S. aureus pathoadaptation and utilising genomics for management of complicated S. aureus infections. The online version of this article (10.1186/s13073-018-0574-x) contains supplementary material, which is available to authorized users.
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影响因子：
3.9
作者：
Duchêne S;Holt KE;Weill FX;Le Hello S;Hawkey J;Edwards DJ;Fourment M;Holmes EC
通讯作者：
Holmes EC
影响因子：
3.7
作者：
Holmes NE;Robinson JO;van Hal SJ;Munckhof WJ;Athan E;Korman TM;Cheng AC;Turnidge JD;Johnson PDR;Howden BP;VANESSA study group, on behalf of the Australasian Society for Infectious Diseases (ASID) Clinical Research Network (CRN)
通讯作者：
VANESSA study group, on behalf of the Australasian Society for Infectious Diseases (ASID) Clinical Research Network (CRN)
影响因子：
10.7
作者：
Minh BQ;Nguyen MA;von Haeseler A
通讯作者：
von Haeseler A
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W