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Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

机译：化脓性筋膜炎炎性环境中化脓性链球菌转录组的变化

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Streptococcus pyogenes is a major cause of necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection. At the host infection site, the local environment and interactions between the host and bacteria have effects on bacterial gene expression profiles, while the gene expression pattern of S. pyogenes related to this disease remains unknown. In this study, we used a mouse model of necrotizing fasciitis and performed RNA-sequencing (RNA-seq) analysis of S. pyogenes M1T1 strain 5448 by isolating total RNA from infected hind limbs obtained at 24, 48, and 96 h postinfection. RNA-seq analysis results identified 483 bacterial genes whose expression was consistently altered in the infected hindlimbs compared to their expression under in vitro conditions. Genes showing consistent enrichment during infection included 306 encoding molecules involved in virulence, carbohydrate utilization, amino acid metabolism, trace-metal transport, and the vacuolar ATPase transport system. Surprisingly, drastic upregulation of 3 genes, encoding streptolysin S precursor (sagA), cysteine protease (speB), and secreted DNase (spd), was noted in the present mouse model (log2 fold change, >6.0, >9.4, and >7.1, respectively). Conversely, the number of consistently downregulated genes was 177, including those associated with the oxidative stress response and cell division. These results suggest that in necrotizing fasciitis, S. pyogenes shows an altered metabolism, decreased cell proliferation, and upregulation of expression of major toxins. Our findings are considered to provide critical information for developing novel treatment strategies and vaccines for necrotizing fasciitis.IMPORTANCE Necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, is principally caused by S. pyogenes. The inflammatory environment at the site of infection causes global gene expression changes for survival of the bacterium and pathogenesis. However, no known study regarding transcriptomic profiling of S. pyogenes in cases of necrotizing fasciitis has been presented. We identified 483 bacterial genes whose expression was consistently altered during infection. Our results showed that S. pyogenes infection induces drastic upregulation of the expression of virulence-associated genes and shifts metabolic pathway usage. In particular, high-level expression of toxins, such as cytolysins, proteases, and nucleases, was observed at infection sites. In addition, genes identified as consistently enriched included those related to metabolism of arginine and histidine as well as carbohydrate uptake and utilization. Conversely, genes associated with the oxidative stress response and cell division were consistently downregulated during infection. The present findings provide useful information for establishing novel treatment strategies.
机译：化脓性链球菌是坏死性筋膜炎的主要原因，坏死性筋膜炎是威胁生命的皮下软组织感染。在宿主感染部位，局部环境以及宿主与细菌之间的相互作用对细菌基因表达谱有影响，而与此疾病相关的化脓性链球菌的基因表达模式仍然未知。在这项研究中，我们使用了一种坏死性筋膜炎的小鼠模型，并通过从感染后24、48和96 h获得的感染后肢中分离总RNA，对化脓性链球菌M1T1菌株5448进行了RNA测序（RNA-seq）分析。 RNA-seq分析结果确定了483个细菌基因，与在体外条件下的表达相比，它们在被感染后肢中的表达一直发生变化。在感染过程中表现出一致富集的基因包括306个编码分子，涉及毒性，碳水化合物利用，氨基酸代谢，微量金属转运和液泡ATPase转运系统。令人惊讶的是，在本小鼠模型中发现了3个编码链球菌溶血素S前体（sagA），半胱氨酸蛋白酶（speB）和分泌的DNase（spd）的基因的上调（log2倍数变化，> 6.0，> 9.4和> 7.1） ， 分别）。相反，持续下调的基因数量为177，其中包括与氧化应激反应和细胞分裂有关的基因。这些结果表明，在坏死性筋膜炎中，化脓性链球菌显示代谢改变，细胞增殖减少和主要毒素表达上调。我们的发现被认为为开发新的治疗坏死性筋膜炎的策略和疫苗提供了重要信息。重要坏死性筋膜炎是一种威胁生命的皮下软组织感染，主要由化脓性链球菌引起。感染部位的炎性环境导致整体基因表达发生变化，从而影响细菌的生存和发病机理。但是，目前尚无关于化脓性筋膜炎病例中化脓性链球菌转录组谱分析的已知研究。我们鉴定了483个细菌基因，其表达在感染过程中一直发生变化。我们的结果表明，化脓性链球菌感染会诱导毒力相关基因表达的急剧上调并改变代谢途径的使用。特别地，在感染部位观察到毒素的高水平表达，例如溶细胞素，蛋白酶和核酸酶。另外，被鉴定为持续富集的基因包括与精氨酸和组氨酸的代谢以及碳水化合物的摄取和利用有关的基因。相反，在感染过程中，与氧化应激反应和细胞分裂相关的基因始终被下调。本发现为建立新的治疗策略提供了有用的信息。

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