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We used murine models of implant\u2010associated biofilm infection and <jats:italic><jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>.\u2009aureus<\/jats:italic> bacteraemia (<jats:styled-content style=\"fixed-case\">SAB<\/jats:styled-content>) to compare virulence of <jats:styled-content style=\"fixed-case\">USA<\/jats:styled-content>300 strain <jats:styled-content style=\"fixed-case\">LAC<\/jats:styled-content>, its isogenic <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> mutant, and derivatives of each of these strains with mutations in all 10 of the genes encoding recognized extracellular proteases. The <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> mutant was attenuated in both models, and this was reversed by eliminating production of extracellular proteases. To examine the mechanistic basis, we identified proteins impacted by <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> in a protease\u2010dependent manner. We identified 253 proteins where accumulation was reduced in the <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> mutant compared with the parent strain, and was restored in the <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content>\/protease mutant. Additionally, in <jats:styled-content style=\"fixed-case\">SAB<\/jats:styled-content>, the <jats:styled-content style=\"fixed-case\">LAC<\/jats:styled-content> protease mutant exhibited a hypervirulent phenotype by comparison with the isogenic parent strain, demonstrating that <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> also positively regulates production of virulence factors, some of which are subject to protease\u2010mediated degradation. We propose a model in which attenuation of <jats:styled-content style=\"fixed-case\"><jats:italic>sarA<\/jats:italic><\/jats:styled-content> mutants is defined by their inability to produce critical factors and simultaneously repress production of extracellular proteases that would otherwise limit accumulation of virulence factors.<\/jats:p>","DOI":"10.1111\/mmi.12048","type":"journal-article","created":{"date-parts":[[2012,10,18]],"date-time":"2012-10-18T18:35:04Z","timestamp":1350585304000},"page":"1183-1196","source":"Crossref","is-referenced-by-count":111,"title":["<scp><i>sarA<\/i><\/scp>\u2010mediated repression of protease production plays a key role in the pathogenesis of <i><scp>S<\/scp>taphylococcus aureus<\/i><scp>USA<\/scp>300 isolates"],"prefix":"10.1111","volume":"86","author":[{"given":"Agnieszka K.","family":"Zielinska","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology University of Arkansas for Medical Sciences  Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Beenken","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Arkansas for Medical Sciences  Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara N.","family":"Mrak","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Arkansas for Medical Sciences  Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horace J.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Arkansas for Medical Sciences  Little Rock AR 72205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginell R.","family":"Post","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Arkansas for Medical Sciences  Little Rock AR 72205 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