MRSA lineage USA300 isolated from bloodstream infections exhibit altered virulence regulation

The epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 lineage has recently become a leading cause of hospital-associated bloodstream infections (BSIs). Here, we leveraged this recent introduction into hospitals and the limited genetic variation across USA300 isolates to identify mutations that contribute to its success in a new environment. We found that USA300 BSI isolates exhibit altered virulence regulation. Using comparative genomics to delineate the genes involved in this phenotype, we discovered repeated and independent mutations in the transcriptional regulator sarZ. Mutations in sarZ resulted in increased virulence of USA300 BSI isolates in a murine model of BSI. The sarZ mutations derepressed the expression and production of the surface protein ClfB, which was critical for the pathogenesis of USA300 BSI isolates. Altogether, these findings highlight ongoing evolution of a major MRSA lineage and suggest USA300 strains can optimize their fitness through altered regulation of virulence. [Display omitted] •Bloodstream infection USA300 isolates have evolved altered virulence regulation•Altered virulence is associated with mutations in the transcription factor SarZ•Mutating sarZ leads to hypervirulence in a murine bloodstream infection model•ClfB contributes to the hypervirulence of sarZ mutant USA300 isolates Staphylococcus aureus is a versatile pathogen. Dyzenhaus et al. show that USA300 clinical isolates from the bloodstream naturally acquire mutations in the transcription factor SarZ that increase their virulence in a murine model of bloodstream infection. This study highlights the power of genomics to discover new biology in infectious disease.