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aureus<\/jats:italic>\n                    and\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    leads to worsened disease severity compared to mono-microbial infection. Because our understanding of the mechanisms driving enhanced disease severity during co-infection is incomplete, 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 toward host cells. We determined that\n                    <jats:italic>C. albicans<\/jats:italic>\n                    enhances\n                    <jats:italic>S. aureus<\/jats:italic>\n                    cytotoxicity toward both murine and human monocytes. These data revealed that enhanced murine monocyte cell death requires the\n                    <jats:italic>S. aureus<\/jats:italic>\n                    Agr virulence regulatory system, and cell death is driven by \u03b1-type phenol soluble modulins and \u03b3-hemolysin. Unexpectedly, upon testing human monocytes 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 in mono-culture and toward murine cells. Human neutrophils are also susceptible to this cytotoxicity. 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. We observed similar cytotoxicity phenotypes using clinical isolates of both\n                    <jats:italic>S. aureus<\/jats:italic>\n                    and\n                    <jats:italic>C. albicans<\/jats:italic>\n                    , demonstrating broad conservation of this interaction. Finally, using mice that express the human isoform of the PVL receptor, we found that\n                    <jats:italic>C. albicans<\/jats:italic>\n                    enhances virulence of\n                    <jats:italic>S. aureus<\/jats:italic>\n                    \u0394\n                    <jats:italic>agr<\/jats:italic>\n                    during co-infection. Overall, this study determined that\n                    <jats:italic>C. albicans<\/jats:italic>\n                    enhances\n                    <jats:italic>S. aureus<\/jats:italic>\n                    toxin-mediated host cell death, and co-culture engages a major virulence regulatory system in a typically non-toxic\n                    <jats:italic>S. aureus<\/jats:italic>\n                    strain to induce potent human-selective cytotoxicity.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014490","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T17:41:53Z","timestamp":1785951713000},"page":"e1014490","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4532-9486","authenticated-orcid":true,"given":"Kara R.","family":"Eichelberger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravishankar","family":"Chandrasekaran","sequence":"additional","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":"Saikat","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie 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