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STSS isolates have been previously shown to have high frequency mutations in the<jats:italic>csrS\/csrR<\/jats:italic>(<jats:italic>covS\/covR<\/jats:italic>) and\/or<jats:italic>rgg<\/jats:italic>(<jats:italic>ropB<\/jats:italic>) genes, which are negative regulators of virulence. However, these mutations were found at somewhat low frequencies in<jats:italic>emm1<\/jats:italic>-genotyped isolates, the most prevalent STSS genotype. In this study, we sought to detect causal mutations of enhanced virulence in<jats:italic>emm1<\/jats:italic>isolates lacking mutation(s) in the<jats:italic>csrS\/csrR<\/jats:italic>and<jats:italic>rgg<\/jats:italic>genes. Three mutations associated with elevated virulence were found in the<jats:italic>sic<\/jats:italic>(a virulence gene) promoter, the<jats:italic>csrR<\/jats:italic>promoter and the<jats:italic>rocA<\/jats:italic>gene (a<jats:italic>csrR<\/jats:italic>positive regulator).<jats:italic>In vivo<\/jats:italic>contribution of the<jats:italic>sic<\/jats:italic>promoter and<jats:italic>rocA<\/jats:italic>mutations to pathogenicity and lethality was confirmed in a GAS mouse model. Frequency of the<jats:italic>sic<\/jats:italic>promoter mutation was significantly higher in STSS<jats:italic>emm1<\/jats:italic>isolates than in non-invasive STSS isolates; the<jats:italic>rocA<\/jats:italic>gene mutation frequency was not significantly different among STSS and non-STSS isolates. STSS<jats:italic>emm1<\/jats:italic>isolates possessed a high frequency mutation in the<jats:italic>sic<\/jats:italic>promoter. Thus, this mutation may play a role in the dynamics of virulence and STSS pathogenesis.<\/jats:p>","DOI":"10.1038\/srep28761","type":"journal-article","created":{"date-parts":[[2016,6,28]],"date-time":"2016-06-28T09:18:41Z","timestamp":1467105521000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Spontaneous mutations in Streptococcus pyogenes isolates from streptococcal toxic shock syndrome patients play roles in virulence"],"prefix":"10.1038","volume":"6","author":[{"given":"Tadayoshi","family":"Ikebe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Matsumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisako","family":"Nihonmatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Ohya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rumi","family":"Okuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieko","family":"Mitsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuji","family":"Kawahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Kameyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Shimada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Ato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohnishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,28]]},"reference":[{"key":"BFsrep28761_CR1","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1128\/CMR.13.3.470","volume":"13","author":"MW Cunningham","year":"2000","unstructured":"Cunningham, M. 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