Comparative mortality of dominant Staphylococcus aureus lineages in human bacteremia and animal infection models.

Staphylococcus aureus is a major human pathogen responsible for severe infections, including infective endocarditis. While host factors influencing disease outcome are well characterized, lineage-specific virulence mechanisms remain poorly defined. Herein, we investigated eighty-nine bacteremic S. aureus isolates from nine globally distributed lineages using Galleria mellonella and rabbit infection models, alongside phenotypic and transcriptomic analyses. Despite marked genotypic and phenotypic heterogeneity, mortality in G. mellonella varied significantly between lineages and correlated with hemolytic activity. ST398 isolates demonstrated heightened larval virulence linked to increased α- and δ-hemolysin production, whereas CC30 strains exhibited reduced growth, biofilm formation and infectivity. The ST398 agrC mutant Sau7 displayed a distinct phenotype, with elevated biofilm production but attenuated larval virulence. However, in the rabbit endocarditis model, Sau7 exhibited mortality rates similar to other ST398 isolates and was associated with larger vegetations and higher bacterial burdens, underscoring the role of the agr system in colonization and biofilm development. Transcriptomic profiling highlighted quorum-sensing pathways and hemolysin expression as key drivers of virulence in ST398 strains. Our findings reveal clear lineage-specific differences in S. aureus pathogenicity and demonstrate that virulence is context dependent, varying across infection models. These results emphasize the importance of using complementary in vivo systems to capture the multifaceted nature of S. aureus disease potential and to better predict infection outcomes.