Programmed in vivo excision of prophage φ13 is an essential timing device for the Staphylococcus aureus infectious process

Mobile genetic elements play an essential part in the infectious process of major pathogens, yet the role of prophage dynamics in Staphylococcus aureus remains poorly understood. Here we studied the impact of the φ13 hlb-converting prophage, whose integration inactivates the hlb β-toxin gene, on staphylococcal pathogenesis. We showed that prophage φ13 is lost in approximately half the bacterial population during the course of infection. Inactivation of the φ13 int recombinase gene, essential for insertion/excision, locked the prophage in the bacterial chromosome, leading to a significant loss of virulence in a murine systemic infection model. In contrast, the non-lysogen strain (Δφ13), where the hlb beta-hemolysin gene is reconstituted, displayed strongly increased virulence. Accordingly, histopathological analyses revealed more severe nephritis in mice infected with bacteria lacking prophage φ13 (Δφ13), in contrast to infection with the parental strain and particularly with the Δint mutant, which led to less severe renal lesions. Cytokine induction in a human neutrophil model showed significantly increased IL-6 expression following infection with the beta-hemolysin producing strain (Δφ13). Our results indicate that programmed in vivo excision of the φ13 prophage is essential for progression of the Staphylococcus aureus infectious process, since early excision rapidly kills the host whereas the absence of excision significantly lowers staphylococcal virulence.