SRP080084 PRJNA335565 Mono and coculture transcriptome analyses of S. aureus JE2 with or without C. striatum ATCC 6940 Transcriptome Staphylococcus aureus–human interactions result in a continuum of outcomes from commensalism to pathogenesis. S. aureus is a clinically important pathogen that asymptomatically colonizes ~25% of humans as a member of the nostril and skin microbiota, residing with Corynebacterium and other genera. Corynebacterium species routinely share skin growth environments with S. aureus in the human nasal cavity and also positively correlate together in diabetic foot wounds where S. aureus often forms a chronic infection. Due to these associations, we hypothesized that Corynebacterium may diminish S. aureus virulence, modifying it towards a more commensal lifestyle. We observed a broad shift in S. aureus gene transcription during in vitro growth with the common skin/nasal commensal Corynebacterium striatum, including increased transcription of genes known to exhibit increased expression during human nasal colonization. S. aureus uses several regulatory pathways to transition between commensal and pathogenic states; one of which, the quorum signal accessory gene regulator (agr) system, was strongly inhibited by Corynebacterium spp. Phenotypically, S. aureus exposed to C. striatum exhibited increased adhesion to epithelial cells, reflecting a commensal state, and decreased hemolysin activity, reflecting an attenuation of virulence. Consistent with this, S. aureus displayed diminished fitness in experimental in vivo coinfections. These data support a model in which S. aureus shifts from virulence towards a commensal state when exposed to commensal Corynebacterium species. Staphylococcus aureus