Distinct Phenotypic and Genomic Signatures Underlie Contrasting Pathogenic Potential of Staphylococcus epidermidis Clonal Lineages

Abstract

Background: Staphylococcus epidermidis is a common skin commensal that has emerged as a pathogen in hospitals, mainly related to medical devices-associated infections. Noteworthy, infection rates by S. epidermidis have the tendency to rise steeply in next decades together with medical devices use and immunocompromized population growth. Staphylococcus epidermidis population structure includes two major clonal lineages (A/C and B) that present contrasting pathogenic potentials. To address this distinction and explore the basis of increased pathogenicity of A/C lineage, we performed a detailed comparative analysis using phylogenetic and integrated pangenome-wide-association study (panGWAS) approaches and compared the lineages's phenotypes in in vitro conditions mimicking carriage and infection. Results: Each S. epidermidis lineage had distinct phenotypic signatures in skin and infection conditions and differed in genomic content. Combination of phenotypic and genotypic data revealed that both lineages were well adapted to skin environmental cues. However, they appear to occupy different skin niches, perform distinct biological functions in the skin and use different mechanisms to complete the same function: lineage B strains showed evidence of specialization to survival in microaerobic and lipid rich environment, characteristic of hair follicle and sebaceous glands; lineage A/C strains showed evidence for adaption to diverse osmotic and pH conditions, potentially allowing them to occupy a broader and more superficial skin niche. In infection conditions, A/C strains had an advantage, having the potential to bind blood-associated host matrix proteins, form biofilms at blood pH, resist antibiotics and macrophage acidity and to produce proteases. These features were observed to be rare in the lineage B strains. PanGWAS analysis produced a catalog of putative S. epidermidis virulence factors and identified an epidemiological molecular marker for the more pathogenic lineage. Conclusion: The prevalence of A/C lineage in infection is probably related to a higher metabolic and genomic versatility that allows rapid adaptation during transition from a commensal to a pathogenic lifestyle. The putative virulence and phenotypic factors associated to A/C lineage constitute a reliable framework for future studies on S. epidermidis pathogenesis and the finding of an epidemiological marker for the more pathogenic lineage is an asset for the management of S. epidermidis infections.

Keywords: GWAS; S. epidermidis; clonal lineages; commensal; pan genome; pathogen.

FIGURE 1

Maximum-likelihood tree of the 82 S. epidermidis strains. The tree was generated by RaxML (Stamatakis et al., 2012) embedded in Gubbins (Croucher et al., 2015), based on the core gene alignment with removal of the recombining regions. In blue are depicted the colonization isolates, in red the infection isolates and in gray are the isolates for which no epidemiological information was available. (A–C) Correspond to S. epidermidis clonal clusters, according to Meric et al. (2015).

FIGURE 2

Performance of cluster A/C and B strains in the growth and biofilm assays. (A) Average growth rates for A/C and B strains grown in liquid medium at pH 4.5; (B) Average growth rates for A/C and B strains grown in liquid medium with 2M NaCl; (C) Average biofilm formation capacity for A/C and B strains at pH 5.5; (D) Average biofilm formation capacity for A/C and B strains at pH 7.

FIGURE 3

Ecological model of cluster A/C and B strains during a catheter-associated infection. This model was based on the pangenomic wide association studies and phenotypic results performed within this study. In each text box are listed the traits associated to each cluster that are important for survival and adaptation in a specific niche. A/C strains are represented by blue circles and B strains are represented by green circles.