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How CovRS mutations enhance systemic dissemination is not well understood. A hypervirulent GAS isolate of the<jats:italic>emm<\/jats:italic>3 genotype, MGAS315, was characterized using a mouse model of pulmonary infection to understand systemic dissemination. This strain has a G1370T mutation in the sensor kinase<jats:italic>covS<\/jats:italic>gene of CovRS. Intratracheal inoculation of MGAS315 led to the lung infection that displayed extensive Gram staining at the alveolar ducts, alveoli, and peribronchovascular and perivascular interstitium. The correction of the<jats:italic>covS<\/jats:italic>mutation did not alter the infection at the alveolar ducts and alveoli but prevented GAS invasion of the peribronchovascular and perivascular interstitium. Furthermore, the<jats:italic>covS<\/jats:italic>mutation allowed MGAS315 to disrupt and degrade the smooth muscle and endothelial layers of the blood vessels, directly contributing to systemic dissemination. It is concluded that hypervirulent<jats:italic>emm<\/jats:italic>3 GAS<jats:italic>covS<\/jats:italic>mutants can invade the perivascular interstitium and directly attack the vascular system for systemic dissemination.<\/jats:p>","DOI":"10.1128\/iai.00080-18","type":"journal-article","created":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T13:31:36Z","timestamp":1522416696000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Hypervirulent Group A Streptococcus of Genotype<i>emm<\/i>3 Invades the Vascular System in Pulmonary Infection of Mice"],"prefix":"10.1128","volume":"86","author":[{"given":"Benfang","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan","family":"Minor","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenchao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70267-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw248"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/338466"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000832"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1016282108"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.01057.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.10.5298-5305.1999"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.12.3649-3657.1999"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/319291"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0020005"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/651019"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01218-12"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01458-13"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129417"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00790-16"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00530-17"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0407247"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.4049\/jimmunol.145.4.1251","article-title":"Synthetic peptide vaccine against mucosal colonization by group A streptococci. 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