A bacterial pigment provides cross-species protection from H₂O₂- and neutrophil-mediated killing.

Abstract

Bacterial infections are often polymicrobial. <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> cause chronic co-infections, which are more problematic than mono-species infections. Understanding the mechanisms of their interactions is crucial for treating co-infections. Staphyloxanthin (STX), a yellow pigment synthesized by the <i>S. aureus crt</i> operon, promotes <i>S. aureus</i> resistance to oxidative stress and neutrophil-mediated killing. We found that STX production by <i>S. aureus</i>, either as surface-grown macrocolonies or planktonic cultures, was elevated when exposed to the <i>P. aeruginosa</i> exoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). This was observed with both mucoid and non-mucoid <i>P. aeruginosa</i> strains. The induction phenotype was found in a majority of <i>P. aeruginosa</i> and <i>S. aureus</i> clinical isolates examined. When subjected to hydrogen peroxide or human neutrophils, <i>P. aeruginosa</i> survival was significantly higher when mixed with wild-type (WT) <i>S. aureus</i>, compared to <i>P. aeruginosa</i> alone or with an <i>S. aureus crt</i> mutant deficient in STX production. In a murine wound model, co-infection with WT <i>S. aureus</i>, but not the STX-deficient mutant, enhanced <i>P. aeruginosa</i> burden and disease compared to mono-infection. In conclusion, we identified a role for <i>P. aeruginosa</i> HQNO mediating polymicrobial interactions with <i>S. aureus</i> by inducing STX production, which consequently promotes resistance to the innate immune effectors H₂O₂ and neutrophils. These results further our understanding of how different bacterial species cooperatively cause co-infections.