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

表皮葡萄球菌是人类皮肤和鼻部微生物群的主要成员，也是机会性感染的常见原因。一些克隆谱系在与医疗保健相关的感染中被严重过度表达，但这些克隆的特殊定植、传播和毒力特征的原因尚不清楚。许多表皮葡萄球菌感染很难治疗，因为大多数菌株携带可移动遗传元件(MGE)SCCmec，该基因对大多数β-内酰胺类抗生素具有耐药性。SCCmec可以通过转导噬菌体将SCCmec转移到侵袭性致病菌金黄色葡萄球菌上，从而促进耐甲氧西林金黄色葡萄球菌(MRSA)的进化。然而，这些噬菌体通常是严格的物种特异性的，它们是如何完成MGES从表皮葡萄球菌转移到金黄色葡萄球菌的仍然是个谜。我们在上海和图宾根的研究小组在葡萄球菌的生物学和致病性方面进行了多年的合作。项目合作伙伴Tübingen报告说，转导噬菌体使用葡萄球菌表面糖共聚物壁磷壁酸(WTA)的物种特定结构来识别同源宿主细菌。未发表的数据表明，大约10%的表皮葡萄球菌分离株，其中包括许多与医疗保健相关的克隆，含有额外的遗传元件tarIJLM，使它们能够产生金黄色葡萄球菌类型的WTA，并允许金黄色葡萄球菌噬菌体感染和MGE转移。此外，tarIJLM的表达显著减少了表皮葡萄球菌与上皮细胞的结合，这支持了我们之前关于WTA结构在鼻部定植中的关键作用的发现，并表明WTA结构的变异可能有助于从共生行为向病原体行为的转变。这些发现得到了项目合作伙伴上海的证实，他阐明了与医疗保健相关的金黄色葡萄球菌克隆的进化，并证明了tarIJLM的缺失消除了表皮葡萄球菌在小鼠体内的毒力。我们提出了一种多方面的合作研究方法，研究tarIJLM介导的WTA对表皮葡萄球菌定植人类上皮、逃避免疫识别以及与金黄色葡萄球菌交换MGES能力的作用。将构建一组明确的表皮葡萄球菌突变体，并阐明WTA介导的上皮细胞结合的结构-活性关系。此外，将在体外和体内感染模型中探索tarIJLM改变的WTA对人类抗体和补体系统识别的影响。从人类皮肤、鼻子和感染中分离出的大量表皮葡萄球菌将被描述为将单个WTA结构与表皮葡萄球菌栖息地特异性和侵袭性联系起来。我们的项目应该有助于揭开一种主要人类病原体的生态和进化，并为控制表皮葡萄球菌感染创造新的途径。

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 Unpublished data indicate that ca. 10% of the S. epidermidis isolates, among them many healthcare-associated clones, contain an additional genetic element, tarIJLM, which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.