Integrative genomic, virulence, and transcriptomic analysis of emergent Streptococcus dysgalactiae subspecies equisimilis (SDSE) emm type stG62647 isolates causing human infections.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-11-13 Epub Date: 2024-10-17 DOI:10.1128/mbio.02578-24
Jesus M Eraso, Randall J Olsen, S Wesley Long, Ryan Gadd, Sarrah Boukthir, Ahmad Faili, Samer Kayal, James M Musser
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Abstract

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is a Gram-positive bacterial pathogen that infects humans and is closely related to group A streptococcus (GAS). Compared with GAS, far less is known about SDSE pathobiology. Increased rates of invasive SDSE infections have recently been reported in many countries. One SDSE emm type (stG62647) is known to cause severe diseases, including necrotizing soft-tissue infections, endocarditis, and osteoarticular infections. To increase our understanding of the molecular pathogenesis of stG62647 SDSE isolates causing human infections, we sequenced to closure the genomes of 120 stG62647 SDSE isolates. The genomes varied in size from 2.1 to 2.24 Mb pairs. The great majority of stG62647 isolates had IS1548 integrated into the silB gene, thereby inactivating it. Regions of difference, such as mobile genetic elements, were the largest source of genomic diversity. All 120 stG62647 isolates were assayed for virulence using a well-established mouse model of necrotizing myositis. An unexpectedly wide range of virulence was identified (20% to 95%), as assessed by near-mortality data. To explore the molecular mechanisms underlying virulence differences, we analyzed RNAseq transcriptome profiles for 38 stG62647 isolates (comprising the 19 least and most virulent) grown in vitro. Genetic polymorphisms were identified from whole-genome sequence data. Collectively, the results suggest that these SDSE isolates use multiple genetic pathways to alter virulence phenotype. The data also suggest that human genetics and underlying medical conditions contribute to disease severity. Our study integrates genomic, mouse virulence, and RNAseq data to advance our understanding of SDSE pathobiology and its molecular pathogenesis.

Importance: This study integrated genomic sequencing, mouse virulence assays, and bacterial transcriptomic analysis to advance our understanding of the molecular mechanisms contributing to Streptococcus dysgalactiae subsp. equisimilis emm type stG62647 pathogenesis. We tested a large cohort of genetically closely related stG62647 isolates for virulence using an established mouse model of necrotizing myositis and discovered a broad spectrum of virulence phenotypes, with near-mortality rates ranging from 20% to 95%. This variation was unexpected, given their close genetic proximity. Transcriptome analysis of stG62647 isolates responsible for the lowest and highest near-mortality rates suggested that these isolates used multiple molecular pathways to alter their virulence. In addition, some genes encoding transcriptional regulators and putative virulence factors likely contribute to SDSE emm type stG62647 pathogenesis. These data underscore the complexity of pathogen-host interactions in an emerging SDSE clonal group.

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对引起人类感染的新出现的赤痢链球菌马氏亚种(SDSE)emm 型 stG62647 分离物进行基因组、毒力和转录组综合分析。
赤痢链球菌马氏亚种(SDSE)是一种感染人类的革兰氏阳性细菌病原体,与 A 组链球菌(GAS)密切相关。与 GAS 相比,人们对 SDSE 病理生物学的了解要少得多。最近,许多国家都报告了侵袭性 SDSE 感染率上升的情况。已知一种 SDSE emm 型(stG62647)可导致严重疾病,包括坏死性软组织感染、心内膜炎和骨关节感染。为了进一步了解导致人类感染的 stG62647 SDSE 分离物的分子致病机理,我们对 120 株 stG62647 SDSE 分离物的基因组进行了测序和封闭。这些基因组的大小从 2.1 到 2.24 Mb 对不等。绝大多数 stG62647 分离物的 IS1548 都整合到了 silB 基因中,从而使其失活。移动遗传因子等差异区是基因组多样性的最大来源。利用一种成熟的坏死性肌炎小鼠模型对所有 120 个 stG62647 分离物进行了毒力测定。根据近乎死亡的数据评估,病毒的毒力范围出乎意料地广(20% 到 95%)。为了探索毒力差异的分子机制,我们分析了体外培养的 38 株 stG62647 分离物(包括 19 株毒力最低和毒力最高的分离物)的 RNAseq 转录组图谱。从全基因组序列数据中确定了基因多态性。总之,研究结果表明,这些 SDSE 分离物利用多种遗传途径来改变毒力表型。数据还表明,人类遗传学和潜在的医疗条件对疾病的严重程度有影响。我们的研究整合了基因组、小鼠毒力和 RNAseq 数据,以促进我们对 SDSE 病理生物学及其分子发病机制的了解:本研究整合了基因组测序、小鼠毒力测定和细菌转录组分析,以加深我们对导致赤痢链球菌亚种马痢疾杆菌emm型stG62647发病机制的分子机制的理解。我们使用已建立的坏死性肌炎小鼠模型测试了一大批基因密切相关的 stG62647 分离物的毒力,结果发现了广泛的毒力表型,近致死率从 20% 到 95% 不等。鉴于它们的基因非常接近,这种差异出乎意料。对造成最低和最高近致死率的 stG62647 分离物的转录组分析表明,这些分离物利用多种分子途径来改变其毒力。此外,一些编码转录调节因子和假定毒力因子的基因可能有助于 SDSE emm 型 stG62647 的致病。这些数据强调了新出现的 SDSE 克隆组中病原体与宿主相互作用的复杂性。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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