Differential pathogenic and commensal response of Staphylococcus aureus and Staphylococcus epidermidis toward chemical signals of human skin

Abstract

Pathogenic Staphylococcus aureus and commensal Staphylococcus epidermidis encounter acidic pH and C16 fatty acids on human skin and are known to produce orthologous serine proteases SspA and Esp with documented pro-inflammatory roles. Using protease production as a potential biomarker of pathogenic and commensal phenotypes, we have conducted a detailed analysis of how S. aureus and S. epidermidis respond to C16 fatty acids at acidic pH. During growth at pH 5.5, palmitoleic acid C16:1 was more toxic to S. aureus, but toxicity was mitigated by saturated palmitic acid C16:0. Acidic pH and C16 fatty acids stimulated SspA protease production in S. aureus but repressed Esp in S. epidermidis. Although S. aureus biofilm formation was stimulated by C16:0, this effect was diminished by 25 µM C16:1, which promotes protease production, whereas S. epidermidis maintained strong biofilm in the presence of both C16:0 and C16:1. Exogenous C16:0 was directly incorporated into phospholipid by S. epidermidis but was extended to C18:0 and C20:0 in S. aureus prior to incorporation. This may account for altered signaling through the GraSR two-component sensor, such that in S. aureus, deletion of graS/R caused impaired growth at pH 5.5 in the presence of C16:1, which was restored by complementation with graS/R from S. aureus, but not S. epidermidis. These findings provide a model framework for understanding how S. aureus and S. epidermidis exhibit differential phenotypes, including protease production and biofilm formation in response to combined C16 fatty acids and acidic pH, which promote distinct differences in the remodeling of membrane phospholipid. IMPORTANCE Human skin is a chemically hostile environment, with acidic pH and antimicrobial fatty acids that challenge microbial survival. Understanding how closely related Staphylococcus epidermidis and Staphylococcus aureus navigate these conditions is critical for distinguishing commensal behavior from pathogenic potential. Our research reveals that S. aureus and S. epidermidis, although genetically similar, employ markedly distinct adaptive mechanisms in response to identical skin-derived cues. Specifically, each species remodels its membrane phospholipids in unique ways under acidic pH and C16 fatty acid exposure. These environmental factors also differentially modulate their biofilm formation and protease activity. Together, our findings highlight how the same host-derived chemical signals of skin can activate virulence-associated traits in S. aureus while supporting commensal persistence in S. epidermidis.