The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here we report the comprehensive molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for optimal growth in human blood, confers resistance to neutrophil killing, and degrades neutrophil extracellular traps (NETs). Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the etiology and pathogenesis of scarlet fever-causing GAS mediated by phage ΦHKU.vir exotoxins.

中文翻译：

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噬菌体外毒素增强流行性猩红热化脓性链球菌的定殖适应性

猩红热的再次出现对全球公共卫生构成了新的威胁。东北亚血清型M12（emm12）化脓性链球菌（A群链球菌，GAS）引起猩红热的能力在流行病学上与新的前噬菌体的存在有关，包括编码噬菌体超抗原SSA和SpeC的噬菌体ΦHKU.vir和DNase Spd1。在这里，我们报告ΦHKU.vir编码的外毒素的全面分子表征。我们证明，链球菌溶血素O（SLO）诱导的来自宿主细胞存储的谷胱甘肽外排是一种先前未被认可的GAS毒力机制，可促进SSA的释放和活性，代表了巯基活化细菌超抗原的首次描述。Spd1是人体血液最佳生长所必需的，可赋予对嗜中性粒细胞杀灭的抵抗力，并降解嗜中性粒细胞胞外陷阱（NETs）。调查ΦHKU.vir编码的外毒素的单，双和三同基因敲除突变体，我们发现SpeC和Spd1协同作用以促进小鼠模型中的鼻咽定植。这些结果提供了由噬菌体ΦHKU.vir外毒素介导的猩红热致GAS的病因和发病机理的见解。