Host DNA damage and cellular fate in bacterial infections, with a focus on Staphylococcus aureus

Abstract Staphylococcus aureus, a leading human pathogen, is increasingly recognized as a genotoxic bacterium that reshapes host cell integrity beyond its classical virulence traits. By inducing DNA damage in host cells, S. aureus activates host DNA damage response (DDR) pathways that can determine the balance between bacterial clearance and persistence. By promoting chromatin remodeling and epigenetic reprogramming, through bacterial effectors such as phenol-soluble modulins and infection-induced metabolic changes, S. aureus modulates host immune responses and supports intracellular persistence. These interconnected mechanisms link DNA damage with immune evasion, chronic inflammation, and long-term tissue remodeling, which may contribute to carcinogenesis in chronically infected tissues. Recognizing S. aureus as both an infectious and genotoxic agent opens new therapeutic perspectives. Targeting DDR and epigenetic pathways, or modulating trained immunity to restore protective responses, offers promising strategies to counteract bacterial persistence and limit infection-associated pathologies. This integrative perspective redefines the pathogenesis of S. aureus by linking its genotoxic activity to host cellular reprogramming, and underscores the potential of host-directed therapeutic strategies as complementary approaches to conventional antibiotic treatment. It establishes a conceptual framework for understanding S. aureus persistence and pathogenicity in the context of rising antibiotic resistance.