Transmissible <i>Staphylococcus pseudintermedius</i> thwarts neutrophil extracellular trap-driven containment to promote invasive disease

Methicillin-resistant <i>Staphylococcus pseudintermedius</i> (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 <i>S. pseudintermedius</i> infections in humans. However, immuno-evasive maneuvers that shape <i>S. pseudintermedius</i> pathogenicity and survival in diseased hosts remain enigmatic. Powered by multi-tech imaging and a mouse model of bloodstream infection, we illustrate that <i>S. pseudintermedius</i> 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 <i>S. pseudintermedius</i> 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.