Population Genomics of emm4 Group A Streptococcus Reveals Progressive Replacement with a Hypervirulent Clone in North America.
Population Genomics of emm4 Group A Streptococcus Reveals Progressive Replacement with a Hypervirulent Clone in North America.
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DOI：
10.1128/msystems.00495-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Flores AR
中科院分区：
文献类型：
--
作者：
DebRoy S;Sanson M;Shah B;Regmi S;Vega LA;Odo C;Sahasrabhojane P;McGeer A;Tyrrell GJ;Fittipaldi N;Shelburne SA;Flores AR
克隆替代是细菌性疾病流行病学变化的主要驱动因素。最近，有人提出，A群链球菌（GAS）偶然出现的新型高毒性克隆是由于获得了一个36kb的DNA区域，导致细胞毒素Nga （NADase）和SLO （streptolyysin O）的表达增加。我们之前描述了一个基因融合事件，涉及编码GAS M蛋白（emm）的基因和邻近的M样蛋白（enn）在emm4 GAS群体中，这是一种缺乏透明质酸胶囊的GAS emm型。通过对1126株具有时间和地理多样性的菌株进行全基因组测序，研究人员发现，到2017年，北美emm4 GAS种群经历了克隆替代，新出现的GAS菌株完全取代了历史上的分离株。新兴的emm4 GAS菌株含有少量的遗传变异，包括emm-enn基因融合，与历史菌株相比，显示出明显的体外生长缺陷。与先前描述的其他GAS克隆替代事件相比，新兴的emm4 GAS菌株没有通过获取外源DNA来定义，并且通过RNA测序和实时定量PCR分析，相对于历史菌株，nga和slow toxin基因的转录水平没有显著增加。尽管体外生长存在差异，但与历史菌株相比，新兴的emm4 GAS菌株在小鼠和人血液中的体外生长具有高毒力。因此，这些数据详细说明了由小的内源性遗传变异定义的高毒囊性GAS克隆的出现和传播，从而定义了一种新的GAS菌株替代模型。由A群链球菌（GAS）引起的严重侵袭性感染在全世界儿童和成人中导致大量发病率和死亡率。以前，GAS克隆菌株替换归因于外源DNA的获取导致新的毒力基因获得或毒力基因表达增加。我们对emm4型GAS的研究发现了一个高毒性GAS分支的出现，该分支由内源DNA含量的变化和相对于替代菌株缺乏增强的毒素基因表达来定义。这些发现扩大了我们对细菌克隆出现的分子机制的理解。
Clonal replacement is a major driver for changes in bacterial disease epidemiology. Recently, it has been proposed that episodic emergence of novel, hypervirulent clones of group A Streptococcus (GAS) results from acquisition of a 36-kb DNA region leading to increased expression of the cytotoxins Nga (NADase) and SLO (streptolysin O). We previously described a gene fusion event involving the gene encoding the GAS M protein (emm) and an adjacent M-like protein (enn) in the emm4 GAS population, a GAS emm type that lacks the hyaluronic acid capsule. Using whole-genome sequencing of a temporally and geographically diverse set of 1,126 isolates, we discovered that the North American emm4 GAS population has undergone clonal replacement with emergent GAS strains completely replacing historical isolates by 2017. Emergent emm4 GAS strains contained a handful of small genetic variations, including the emm-enn gene fusion, and showed a marked in vitro growth defect compared to historical strains. In contrast to other previously described GAS clonal replacement events, emergent emm4 GAS strains were not defined by acquisition of exogenous DNA and had no significant increase in transcript levels of nga and slo toxin genes via RNA sequencing and quantitative real-time PCR analysis relative to historic strains. Despite the in vitro growth differences, emergent emm4 GAS strains were hypervirulent in mice and ex vivo growth in human blood compared to historical strains. Thus, these data detail the emergence and dissemination of a hypervirulent acapsular GAS clone defined by small, endogenous genetic variation, thereby defining a novel model for GAS strain replacement. IMPORTANCE Severe invasive infections caused by group A Streptococcus (GAS) result in substantial morbidity and mortality in children and adults worldwide. Previously, GAS clonal strain replacement has been attributed to acquisition of exogenous DNA leading to novel virulence gene acquisition or increased virulence gene expression. Our study of type emm4 GAS identified emergence of a hypervirulent GAS clade defined by variation in endogenous DNA content and lacking augmented toxin gene expression relative to replaced strains. These findings expand our understanding of the molecular mechanisms underlying bacterial clonal emergence.