Staphylococcus aureus thermonuclease NucA is a pathogenicity factor for septic arthritis and rhodomyrtone resistance mechanism

Abstract

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 Δnuc1 mutant was much less pathogenic and the severity of clinical septic arthritis was markedly reduced, including decreased weight loss, lower kidney bacterial loads, reduced bone erosion, and much less IL-6 production. In vitro, S. aureus genomic DNA induced a robust TNF-α response in macrophage-like RAW 264.7 cells abrogated when the DNA was degraded by NucA. Moreover, the wild type induced high levels of TNF-α, IL-10, and IL-6 in neutrophils and osteoblast-like SAOS-2 cells, respectively. NucA digests neutrophil extracellular traps and enhances extracellular and intracellular survival of bacteria, ultimately exacerbating septic arthritis.