Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death.

Co-infection with Staphylococcus aureus and Candida albicans 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 C. albicans regulate S. aureus virulence toward host cells. We determined that C. albicans enhances S. aureus cytotoxicity toward both murine and human monocytes. These data revealed that enhanced murine monocyte cell death requires the S. aureus Agr virulence regulatory system, and cell death is driven by α-type phenol soluble modulins and γ-hemolysin. Unexpectedly, upon testing human monocytes we discovered that C. albicans induces robust cytotoxicity of an S. aureus agr mutant (Δagr), 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 S. aureus, and SaeRS is required for human-specific cytotoxicity. We further discovered that the SaeRS-regulated toxin Panton-Valentine Leukocidin (PVL) drives S. aureus Δagr cytotoxicity following co-culture. We observed similar cytotoxicity phenotypes using clinical isolates of both S. aureus and C. albicans, demonstrating broad conservation of this interaction. Finally, using mice that express the human isoform of the PVL receptor, we found that C. albicans enhances virulence of S. aureus Δagr during co-infection. Overall, this study determined that C. albicans enhances S. aureus toxin-mediated host cell death, and co-culture engages a major virulence regulatory system in a typically non-toxic S. aureus strain to induce potent human-selective cytotoxicity.