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Because our understanding of the mechanisms driving enhanced disease severity during co-infection is limited, we sought to evaluate how interactions with\n                  <jats:italic>C. albicans<\/jats:italic>\n                  regulate\n                  <jats:italic>S. aureus<\/jats:italic>\n                  virulence towards host cells. We determined that\n                  <jats:italic>C. albicans<\/jats:italic>\n                  enhances\n                  <jats:italic>S. aureus<\/jats:italic>\n                  cytotoxicity towards murine monocytes via a mechanism requiring the Agr system. Agr is a major regulator of\n                  <jats:italic>S. aureus<\/jats:italic>\n                  virulence factors and was previously shown to be activated by\n                  <jats:italic>C. albicans,<\/jats:italic>\n                  but the Agr-regulated virulence factors driving immune cell death are unknown. We identified that enhanced murine monocyte cell death requires the \u03b1-type phenol soluble modulins and \u03c8-hemolysin. Because several\n                  <jats:italic>S. aureus<\/jats:italic>\n                  toxins have species-specific effects, we also tested how co-culture impacts cytotoxicity towards human monocytes. Unexpectedly, we discovered that\n                  <jats:italic>C. albicans<\/jats:italic>\n                  induces robust cytotoxicity of an\n                  <jats:italic>S. aureus agr<\/jats:italic>\n                  mutant (\u0394\n                  <jats:italic>agr<\/jats:italic>\n                  ), which is completely non-toxic towards murine monocytes. Using reporter strains and combinatorial mutants, we identified that co-culture activates the SaeRS regulatory system in\n                  <jats:italic>S. aureus,<\/jats:italic>\n                  and SaeRS is required for human-specific cytotoxicity. We further discovered that the SaeRS-regulated toxin Panton-Valentine Leukocidin (PVL) drives\n                  <jats:italic>S. aureus<\/jats:italic>\n                  \u0394\n                  <jats:italic>agr<\/jats:italic>\n                  cytotoxicity following co-culture. Finally, we observed similar cytotoxicity phenotypes using both\n                  <jats:italic>S. aureus<\/jats:italic>\n                  and\n                  <jats:italic>C. albicans<\/jats:italic>\n                  clinical isolates, demonstrating broad conservation of this interaction. Interestingly, the magnitude by which\n                  <jats:italic>C. albicans<\/jats:italic>\n                  isolates induce cytotoxicity of\n                  <jats:italic>S. aureus<\/jats:italic>\n                  \u0394\n                  <jats:italic>agr<\/jats:italic>\n                  varies among strains tested. Overall, this study identifies that\n                  <jats:italic>C. albicans<\/jats:italic>\n                  activates a major\n                  <jats:italic>S. aureus<\/jats:italic>\n                  virulence regulatory system in a typically non-toxic strain, triggering\n                  <jats:italic>S. aureus<\/jats:italic>\n                  to induce potent human-selective cell death.\n                <\/jats:p>","DOI":"10.1101\/2025.10.03.680095","type":"posted-content","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T04:50:14Z","timestamp":1759553414000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Candida albicans<\/i>\n                  activates\n                  <i>Staphylococcus aureus<\/i>\n                  virulence regulatory systems to drive toxin-mediated human cell death"],"prefix":"10.64898","author":[{"given":"Kara R.","family":"Eichelberger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Podar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia A.","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M.","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravishankar","family":"Chandrasekaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saikat","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Bastarache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor J.","family":"Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Cassat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100708101181000_2025.10.03.680095v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(22)02185-7"},{"key":"2025100708101181000_2025.10.03.680095v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00134-14"},{"key":"2025100708101181000_2025.10.03.680095v1.3","doi-asserted-by":"crossref","unstructured":"Vestergaard M , Frees D , Ingmer H . 2019. 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