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Here we used HLA-transgenic mice to assess the role of both SLO and SLS during both nasopharyngeal and skin infection. Using <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic> MGAS8232 as a model strain, we found that an SLS-deficient strain exhibited a 100-fold reduction in bacterial recovery from the nasopharynx and a 10-fold reduction in bacterial burden in the skin, whereas an SLO-deficient strain did not exhibit any infection defects in these models. Furthermore, depletion of neutrophils significantly restored the bacterial burden of the SLS-deficient bacteria in skin, but not in the nasopharynx. In mice nasally infected with the wildtype <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic>, there was a marked change in localization of the tight junction protein ZO-1 at the site of infection, demonstrating damage to the nasal epithelia that was absent in mice infected with the SLS-deficient strain. Overall, we conclude that SLS is required for the establishment of nasopharyngeal infection and skin infection in HLA-transgenic mice by <jats:italic>S<\/jats:italic>. <jats:italic>pyogenes<\/jats:italic> MGAS8232 and provide evidence that SLS contributes to nasopharyngeal infection through the localized destruction of nasal epithelia.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012072","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T19:01:57Z","timestamp":1709838117000},"page":"e1012072","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Blake A.","family":"Shannon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacklyn 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