The Staphylococcus aureus prophage-encoded SSBP attenuates virulence and enhances IL-6-mediated macrophage clearance

Pathogens often manipulate host immune responses to promote infection. Here, we describe a novel mechanism by which a secreted prophage-encoded single-stranded DNA-binding protein (SSBP) attenuates Staphylococcus aureus virulence while enhancing host immune defenses. SSBP, encoded by the ROSA-like prophage in a colonizing, reduced-virulence strain of S. aureus (NSA1385), significantly increases bacterial susceptibility to macrophage-mediated killing in vitro and reduces pathogenicity in a zebrafish infection model. Treatment with purified recombinant SSBP decreases bacterial survival within macrophages and demonstrates therapeutic potential. Notably, SSBP activates macrophages via interleukin-6 (IL-6), a pro-inflammatory cytokine that promotes bacterial clearance and macrophage activation. These findings uncover an unexpected prophage-derived mechanism in a colonizing S. aureus strain that attenuates virulence while stimulating host immunity, offering promising avenues for anti-infective therapies and immunomodulatory strategies.