Transmissible Staphylococcus pseudintermedius thwarts neutrophil extracellular trap-driven containment to promote invasive disease.

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is an emerging zoonotic pathogen that causes a variety of clinical diseases in mammalian hosts. While it frequently causes infections in dogs and other domestic animals, accumulating evidence indicates that zoonotic spillover and cross-species transmission events favour local and invasive S. pseudintermedius infections in humans. However, immuno-evasive maneuvers that shape S. pseudintermedius pathogenicity and survival in diseased hosts remain enigmatic. Powered by multi-tech imaging and a mouse model of bloodstream infection, we illustrate that S. pseudintermedius adopted a virulence mechanism from predominant bacterial pathogens to surmount neutrophilic responses and neutrophil extracellular trap (NET)-mediated killing. Specifically, release of NucB, a thermostable nuclease, helps MRSP coping with the antimicrobial and pathogen-immobilizing properties of NETs and even promotes intra-neutrophil survival upon phagocytosis, thereby contributing to S. pseudintermedius pathogenesis and persistence within hepatic abscesses. Combined with the analysis of genetically distinct human clinical isolates, all of which display nuclease activity and features of resistance to NETosis-induced killing, our data highlight how zoonotic staphylococci overcome innate immune responses and concurrently uncover a mechanism that may exacerbate animal-borne MRSP infections in humans.