{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:49:02Z","timestamp":1772164142583,"version":"3.50.1"},"reference-count":71,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,8,14]],"date-time":"2015-08-14T00:00:00Z","timestamp":1439510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI087747"],"award-info":[{"award-number":["R01AI087747"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"School of Medicine, University of Nevada"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2015,10]]},"abstract":"Summary<\/jats:title>Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A S<\/jats:italic><\/jats:styled-content>treptococcus<\/jats:italic> (GAS<\/jats:styled-content>) are non\u2010randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M<\/jats:styled-content>3 GAS<\/jats:styled-content> isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA<\/jats:styled-content>. Through use of RNA<\/jats:styled-content>seq analysis, we identified that the natural roc<\/jats:italic>A<\/jats:italic><\/jats:styled-content> mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD<\/jats:styled-content>+<\/jats:sup> hydrolysis. Consequently, an M<\/jats:styled-content>3 GAS<\/jats:styled-content> isolate survived human phagocytic killing at a level 13\u2010fold higher than a roc<\/jats:italic>A<\/jats:italic><\/jats:styled-content> complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA<\/jats:styled-content> functions through the CovR<\/jats:styled-content>\/S<\/jats:styled-content> two\u2010component system as levels of phosphorylated CovR<\/jats:styled-content> increase in the presence of functional RocA<\/jats:styled-content>, and RocA<\/jats:styled-content> has no regulatory activity following cov<\/jats:italic>R<\/jats:italic><\/jats:styled-content> or cov<\/jats:italic>S<\/jats:italic><\/jats:styled-content> mutation. Our data are consistent with RocA<\/jats:styled-content> interfacing with the CovR<\/jats:styled-content>\/S<\/jats:styled-content> two\u2010component system, and that the absence of this activity in M<\/jats:styled-content>3 GAS<\/jats:styled-content> potentiates the severity of invasive infections caused by isolates of this serotype.<\/jats:p>","DOI":"10.1111\/mmi.13136","type":"journal-article","created":{"date-parts":[[2015,7,20]],"date-time":"2015-07-20T09:57:24Z","timestamp":1437386244000},"page":"473-489","source":"Crossref","is-referenced-by-count":45,"title":["Regulatory rewiring confers serotype\u2010specific hyper\u2010virulence in the human pathogen group A S<\/i><\/scp>treptococcus<\/i>"],"prefix":"10.1111","volume":"98","author":[{"given":"Eric W.","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology School of Medicine University of Nevada Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Danger","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology School of Medicine University of Nevada Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anupama B.","family":"Ramalinga","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology School of Medicine University of Nevada Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Horstmann","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases MD Anderson Cancer Center Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel A.","family":"Shelburne","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases MD Anderson Cancer Center Houston Texas 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