From commensalism to pathogenesis: The transcriptional profile of Staphylococcus epidermidis during nasal colonization and prosthetic joint inection

Staphylococcus epidermidis is a common skin commensal that can change from a harmless colonizer to an invasive pathogen, often causing prosthetic joint infections (PJIs). The molecular mechanisms underlying this lifestyle transition are not well understood. Therefore, we conducted ex vivo transcriptional analysis of S. epidermidis from patient-matched nasal swabs and synovial fluid speciments from PJI patients. Gene expression profiles were compared between commensal (nasal) and invasive (synovial fluid) niches using quantitative real-time PCR targeting key virulence, adhesion, immune evasion and metabolic genes. Our analysis revealed environment-specific transcriptional programs underlying the commensal-to- pathogen transition. Three distinct expression patterns were observed: (i) Consistently expressed genes, including immune evasion factors (capC, dltA, and fmtC) and adhesins (sdrG), which showed robust activity in both niches, reflecting fundamental survivial requirements. (ii) Lifestyle-specific genes with differential expression between colonization and infection; and (iii) heterogeneously expressed genes, which suggest strain- or patient-specific adaptation trajectories. Notably, central metabolic genes (fumC, gltA, icd) and the histidine kinase agrC of the Agr quorum sensing system as well as its downstream target gene psm_beta1 showed pronounced downregulation in synovial fluid indicating sufficient exogenous nutrient supply and supports the notion that the bacterium favors a persistence-oriented strategy. Our study provides the first direct ex vivo evidence for environment- specific gene expression patterns tat facilitate S. epidermidis lifestyle transitions advancing our understanding of opportunistic pathogenesis in this clinically important organism.