Structural variation of wall teichoic acid polymers and its role for colonization capacity, virulence, and evolution of Staphylococcus epidermidis

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Staphylococcus epidermidis is a major member of human skin and nasal microbiomes and a frequent cause of opportunistic infections. Some clonal lineages are strongly overrepresented in healthcare-associated infections but reasons for the particular colonization, spreading, and virulence characteristic of these clones have remained unknown. Many S. epidermidis infections are difficult to treat because most strains harbor the mobile genetic element (MGE) SCCmec, which confers resistance to most beta-lactam antibiotics. SCCmec can be transferred to the aggressive pathogen Staphylococcus aureus by transducing phages, which promotes the evolution of methicillin-resistant S. aureus (MRSA). However, such phages are usually strictly species-specific and it has remained mysterious how they accomplish the transfer of MGEs from S. epidermidis to S. aureus.Our research groups in Shanghai and Tübingen collaborate for many years on the biology and pathogenicity of staphylococci. Project partner Tübingen reported that transducing phages use the species-specific structure of wall teichoic acid (WTA), a staphylococcal surface glycopolymer, for recognition of cognate host bacteria. Unpublished data indicate that ca. 10% of the S. epidermidis isolates, among them many healthcare-associated clones, contain an additional genetic element, tarIJLM, which enables them to produce S. aureus-type WTA and allows infection and MGE transfer by S. aureus phages. Moreover, tarIJLM expression strongly reduced S. epidermidis binding to epithelial cells, which supports our previous findings on a crucial role of WTA structure for nasal colonization and suggests that WTA structure variation may contribute to the shift from commensal to pathogen behavior. These findings were corroborated by project partner Shanghai, who elucidated the evolution of healthcare-associated S. aureus clones and demonstrated that deletion of tarIJLM abrogates the virulence of S. epidermidis in mice.We propose a multifaceted collaborative research approach on the role of tarIJLM-mediated WTA modulation for the capacities of S. epidermidis to colonize human epithelia, evade immune recognition, and exchange MGEs with S. aureus. A panel of defined S. epidermidis mutants will be constructed and the structure-activity relationships of WTA-mediated epithelial cell binding will be elucidated. Moreover, the impact of tarIJLM-altered WTA for recognition by human antibodies and complement system will be explored in in vitro and in vivo infection models. Large panels of S. epidermidis isolates from human skin, nose, and infections will be characterized to associate individual WTA structures with S. epidermidis habitat specificity and invasiveness. Our project should help to unravel the ecology and evolution of a major human pathogen and create new avenues for the control of S. epidermidis infections.