Cross-Species Protection to Innate Immunity Mediated by A Bacterial Pigment

Bacterial infections are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus cause chronic co-infections, which are more problematic than mono-species infections. We found that the production of S. aureus membrane-bound pigment staphyloxanthin (STX), was induced by the P. aeruginosa exoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). The induction phenotype was conserved in P. aeruginosa and S. aureus clinical isolates examined. When subjected to hydrogen peroxide or human neutrophils, P. aeruginosa survival was significantly higher when mixed with wild-type (WT) S. aureus, compared to a mutant deficient in STX production or P. aeruginosa alone. In a murine wound model, co-infection with WT S. aureus, but not the STX-deficient mutant, enhanced P. aeruginosa burden and disease compared to mono-infection. In conclusion, we discovered a novel role for P. aeruginosa HQNO mediating polymicrobial interactions with S. aureus by inducing STX production, which consequently promotes resistance of both pathogens to innate immune effectors. These results further our understanding of how different bacterial species cooperatively cause co-infections.