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

壁磷壁酸聚合物的结构变化及其对表皮葡萄球菌定植能力、毒力和进化的作用

• 批准号: 410190180
• 负责人: Professor Dr. Andreas Peschel
• 金额: --
• 依托单位: National Natural Science Foundation of China
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410190180?language=en
• 关键词: Structural; variation; wall; teichoic; acid

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 Unpublished data indicate that ca. 10% of the S. epidermidis isolates, among them many healthcare-associated clones, contain an additional genetic element, tarIJLM, which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

表皮葡萄球菌是人类皮肤和鼻腔微生物组的主要成员，也是机会性感染的常见原因。一些克隆谱系在医疗保健相关感染中所占比例过高，但这些克隆的特定定殖、传播和毒力特征的原因仍不清楚。许多S。表皮感染很难治疗，因为大多数菌株都含有移动的遗传元件（MGE）SCCmec，该元件可赋予对大多数β-内酰胺抗生素的耐药性。SCCmec可通过转导β-内酰胺酶而转移到侵袭性病原体金黄色葡萄球菌中，从而促进耐甲氧西林金黄色葡萄球菌的进化。金黄色葡萄球菌（MRSA）。然而，这些酶通常是严格的种特异性的，它仍然是神秘的，他们是如何完成的MGE从S。epidermidis至S.我们在上海和图宾根的研究团队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，转导细胞利用壁磷壁酸（WTA）的物种特异性结构，一种葡萄球菌表面糖聚合物，用于识别同源宿主细菌。未公布的数据表明，CA。10%的S。表皮葡萄球菌分离株，其中许多与医疗保健相关的克隆，含有一个额外的遗传元件，tarIJLM，使他们能够产生S。金黄色葡萄球菌型WTA，并允许感染和MGE转移的S。金黄色葡萄球菌此外，tarIJLM表达强烈降低S.表皮细胞与上皮细胞结合，这支持了我们先前关于WTA结构对鼻腔定植的关键作用的发现，并表明WTA结构变异可能有助于从鼻腔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，他阐明了医疗保健相关的S。金黄色葡萄球菌克隆并证明tarIJLM的缺失消除了金黄色葡萄球菌的毒力。我们提出了一种多方面的合作研究方法，研究tarIJLM介导的WTA调节S.表皮葡萄球菌能够在人上皮细胞中定植，逃避免疫识别，并与表皮葡萄球菌交换MGE。金黄色。一组定义的S。将构建表皮突变体，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对人抗体和补体系统识别的影响。大型的S。将表征从人皮肤、鼻和感染中分离的表皮葡萄球菌，以将单个WTA结构与S. epidermidis生境特异性和侵袭性。我们的项目应该有助于解开一个主要的人类病原体的生态学和进化，并为控制S。表皮感染