Transcriptional plasticity enables Staphylococcus aureus adaptation to polymicrobial interactions

In the microbial world, survival is not solitary. Staphylococcus aureus thrives or falters depending on its neighbors. This opportunistic pathogen frequently inhabits polymicrobial environments such as chronic wounds, implanted devices, and mucosal surfaces, where interspecies interactions shape its behavior and complicate treatment outcomes. Focusing on the Type VII Secretion System (T7SS), this study explores how S. aureus transcriptionally and functionally adapts during co-culture with three clinically relevant organisms: Pseudomonas aeruginosa , Candida albicans , and Enterococcus faecalis . RNA sequencing revealed distinct ecological responses: P. aeruginosa induced a strongly antagonistic interaction, causing global transcriptional repression, including silencing of virulence genes and T7SS; C. albicans promoted a synergistic response, activating virulence, stress, and metabolic genes despite T7SS repression; and E. faecalis elicited a competitive interaction marked by robust activation of T7SS, cytotoxic effectors, and biosynthetic programs. Western blotting of EsxA validated condition-specific T7SS expression. These findings reveal how S. aureus transcriptionally adapts to microbial neighbors, positioning interspecies signaling as a key driver of precision microbiology and potential target for managing polymicrobial infections.