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The nine\u2010gene GAS locus (<jats:italic>sag<\/jats:italic>A\u2013<jats:italic>sag<\/jats:italic>I) resembling a bacteriocin biosynthetic operon is necessary and sufficient\u200a for\u200a SLS\u200a production.\u200a Using\u200a precise,\u200a in\u2010frame allelic exchange mutagenesis and single\u2010gene complementation, we show <jats:italic>sag<\/jats:italic>A, <jats:italic>sag<\/jats:italic>B, <jats:italic>sag<\/jats:italic>C, <jats:italic>sag<\/jats:italic>D, <jats:italic>sag<\/jats:italic>E, <jats:italic>sag<\/jats:italic>F and <jats:italic>sag<\/jats:italic>G are each individually required for SLS production, and that <jats:italic>sag<\/jats:italic>E may further serve an immunity function. Limited site\u2010directed mutagenesis of specific amino acids in the SagA prepropeptide supports the designation of SLS as a bacteriocin\u2010like toxin. No significant pleotrophic effects of <jats:italic>sag<\/jats:italic>A deletion were observed on M protein, capsule or cysteine protease production. In a murine model of NF, the SLS\u2010negative M1T1 GAS mutant was markedly diminished in its ability to produce necrotic skin ulcers and spread to the systemic circulation. The SLS toxin impaired phagocytic clearance and promoted epithelial cell cytotoxicity, the latter phenotype being enhanced by the effects of M protein and streptolysin O. We conclude that all genetic components of the <jats:italic>sag<\/jats:italic> operon are required for expression of functional SLS, an important virulence factor in the pathogenesis of invasive M1T1 GAS infection.<\/jats:p>","DOI":"10.1111\/j.1365-2958.2005.04583.x","type":"journal-article","created":{"date-parts":[[2005,4,7]],"date-time":"2005-04-07T16:11:27Z","timestamp":1112890287000},"page":"681-695","source":"Crossref","is-referenced-by-count":160,"title":["Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection"],"prefix":"10.1111","volume":"56","author":[{"given":"Vivekanand","family":"Datta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra M.","family":"Myskowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Kwinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"Chiem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nissi","family":"Varki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita G.","family":"Kansal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malak","family":"Kotb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,3,15]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(88)65012-9"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3065"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1128\/jb.91.5.1677-1680.1966","article-title":"Disruption of wall\u2010less bacteria by streptococcal and staphylococcal toxins","volume":"91","author":"Bernheimer A.W.","year":"1966","journal-title":"J Bacteriol"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1128\/jb.93.6.2024-2025.1967","article-title":"Physical behavior of streptolysin S","volume":"93","author":"Bernheimer A.W.","year":"1967","journal-title":"J Bacteriol"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.4.1671-1679.1998"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00576-0"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.11.7029-7038.2001"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-1825-3_172"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.106.3.761"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107401200"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(98)00396-5"},{"key":"e_1_2_6_13_1","unstructured":"Chaffin D.O. 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