Staphylococcus aureus thermonuclease NucA is a key virulence factor in septic arthritis

Septic arthritis, primarily caused by Staphylococcus aureus , poses a significant risk of both mortality and morbidity due to its aggressive nature. The nuc1 -encoded thermonuclease NucA of S. aureus degrades extracellular DNA/RNA, allowing the pathogen to escape neutrophil extracellular traps (NETs) and maintain the infection unabated. Here we show that in the mouse model for hematogenous septic arthritis the Δ nuc1 mutant was much less pathogenic and the severity of clinical septic arthritis was markedly reduced, including decreased weight loss, lower kidney bacterial loads and much less IL-6 production. In vitro, S. aureus genomic DNA induced in macrophages a robust TNF-α response which was abrogated when the DNA was degraded by NucA. NucA induced higher IL-6 production in SAOS-2 and higher TNF-α and IL-10 production in neutrophils and shielded S. aureus from phagocyte engulfment and killing. NucA exacerbates septic arthritis possibly by increased internalization by host cells and killing of neutrophiles.