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At menstruation, the typical acidic vaginal environment rises to near neutral pH, which allows for enhanced TSST\u20101 production. However, the regulatory network which alters toxin production in response to pH is unknown, despite the importance of this cue in the vaginal environment. To mimic the vaginal environment, we used Vaginally Defined Medium to assess TSST\u20101 promoter activity in the mTSS strain\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    MN8 and discovered a significant upregulation of\n                    <jats:italic>tst<\/jats:italic>\n                    expression occurring at pH\u20094.5 in a low glucose environment, referred to here as the acidic virulence surge. This increased expression was observed in several regulatory mutant backgrounds tested, including in the absence of SaeS, which has previously been thought to be required for TSST\u20101 production. Recent studies in non\u2010mTSS\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    strains have identified GraXRS as a pH sensor, in addition to its function in cationic antimicrobial peptide sensing. We therefore hypothesized that GraXRS alters TSST\u20101 expression at low pH. Deletion of the sensor\u2010kinase\n                    <jats:italic>graS<\/jats:italic>\n                    gene resulted in the loss of TSST\u20101 surge at pH\u20094.5, indicating that GraXRS is required for the acidic virulence surge. We also found expression from the SaeRS P1 and SarA promoters to be significantly attenuated in the \u2206\n                    <jats:italic>graS<\/jats:italic>\n                    background. At low pH, the absence of GraS resulted in reduced T cell activation from\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    supernatants when compared to other regulatory mutants, suggesting that GraXRS is the dominant activator at pH\u20094.5. Finally, we developed an in\u00a0vivo murine model to measure\n                    <jats:italic>tst<\/jats:italic>\n                    expression using luciferase expression. Our results demonstrate a complex sequence of events that occur in response to changes in pH and further suggests that GraXRS is the main activator of TSST\u20101 expression at low pH.\n                  <\/jats:p>","DOI":"10.1111\/mmi.70089","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:22:09Z","timestamp":1783488129000},"page":"220-235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elucidating the\n                    <i>Staphylococcus aureus<\/i>\n                    <scp>TSST<\/scp>\n                    \u20101 Regulatory Network as a Response to Vaginal\n                    <scp>pH<\/scp>"],"prefix":"10.1111","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8916-3619","authenticated-orcid":false,"given":"Carla S.","family":"Maduta","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Walton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily P.","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N.","family":"DeJong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9423-2037","authenticated-orcid":false,"given":"Karine","family":"Dufresne","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario Canada"},{"name":"D\u00e9partement des sciences biologiques Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al  Montr\u00e9al Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"McCormick","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry, University of Westen Ontario  London Ontario 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