A novel Staphylococcus aureus cis–trans type I toxin–antitoxin module with dual effects on bacteria and host cells

Bacterial type I toxin–antitoxin (TA) systems are widespread, and consist of a stable toxic peptide whose expression is monitored by a labile RNA antitoxin. We characterized Staphylococcus aureus SprA2/SprA2(AS) module, which shares nucleotide similarities with the SprA1/SprA1(AS) TA system. We demonstrated that SprA2/SprA2(AS) encodes a functional type I TA system, with the cis-encoded SprA2(AS) antitoxin acting in trans to prevent ribosomal loading onto SprA2 RNA. We proved that both TA systems are distinct, with no cross-regulation between the antitoxins in vitro or in vivo. SprA2 expresses PepA2, a toxic peptide which internally triggers bacterial death. Conversely, although PepA2 does not affect bacteria when it is present in the extracellular medium, it is highly toxic to other host cells such as polymorphonuclear neutrophils and erythrocytes. Finally, we showed that SprA2(AS) expression is lowered during osmotic shock and stringent response, which indicates that the system responds to specific triggers. Therefore, the SprA2/SprA2(AS) module is not redundant with SprA1/SprA1(AS), and its PepA2 peptide exhibits an original dual mode of action against bacteria and host cells. This suggests an altruistic behavior for S. aureus in which clones producing PepA2 in vivo shall die as they induce cytotoxicity, thereby promoting the success of the community.