The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom.
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
mBio. 2020 Oct 27;11(5):e02082-20. doi: 10.1128/mBio.02082-20.
Staphylococcal superantigens (SAgs) are a family of secreted toxins that stimulate T cell activation and are associated with an array of diseases in humans and livestock. Most SAgs produced by are encoded by mobile genetic elements, such as pathogenicity islands, bacteriophages, and plasmids, in a strain-dependent manner. Here, we carried out a population genomic analysis of >800 staphylococcal isolates representing the breadth of diversity to investigate the distribution of all 26 identified SAg genes. Up to 14 SAg genes were identified per isolate with the most common gene (encoding a putative SAg, SElW) identified in 97% of isolates. Most isolates (62.5%) have a full-length open reading frame of with an alternative TTG start codon that may have precluded functional characterization of SElW to date. Here, we demonstrate that uses the TTG start codon to translate a potent SAg SElW that induces Vβ-specific T cell proliferation, a defining feature of classical SAgs. SElW is the only SAg predicted to be expressed by isolates of the CC398 lineage, an important human and livestock epidemic clone. Deletion of in a representative CC398 clinical isolate, NM001, resulted in complete loss of T cell mitogenicity , and expression of SElW by increased the bacterial load in the liver during bloodstream infection of SAg-sensitive HLA-DR4 transgenic mice. Overall, we report the characterization of a novel, highly prevalent, and potent SAg that contributes to the pathogenesis of infection. is an important human and animal pathogen associated with an array of diseases, including life-threatening necrotizing pneumonia and infective endocarditis. The success of as a pathogen has been linked in part to its ability to manipulate the host immune response through the secretion of toxins and immune evasion molecules. The staphylococcal superantigens (SAgs) have been studied for decades, but their role in pathogenesis is not well understood, and an appreciation for how SAgs manipulate the host immune response to promote infection may be crucial for the development of novel intervention strategies. Here, we characterized a widely prevalent, previously cryptic, staphylococcal SAg, SElW, that contributes to the severity of infections caused by an important epidemic clone of CC398. Our findings add to the understanding of staphylococcal SAg diversity and function and provide new insights into the capacity of to cause disease.
葡萄球菌超抗原（SAg）是一组分泌型毒素，可刺激 T 细胞活化，并与人类和家畜的一系列疾病有关。大多数由 产生的 SAg 由移动遗传元件（如致病性岛、噬菌体和质粒）以菌株依赖性方式编码。在这里，我们对代表 多样性的 800 多个葡萄球菌分离株进行了群体基因组分析，以研究所有 26 种已鉴定的 SAg 基因的分布。每个分离株可鉴定多达 14 种 SAg 基因，最常见的基因 （编码一种假定的 SAg，SElW）在 97%的分离株中被鉴定。大多数分离株（62.5%）具有完整的 开放阅读框，带有替代的 TTG 起始密码子，这可能导致迄今为止未能对 SElW 的功能进行特征描述。在这里，我们证明 使用 TTG 起始密码子翻译一种有效的 SAg SElW，该 SAg 诱导 Vβ特异性 T 细胞增殖，这是经典 SAg 的定义特征。SElW 是唯一预测由 CC398 谱系分离株表达的 SAg，CC398 是一种重要的人类和家畜流行克隆。在代表 CC398 临床分离株 NM001 中缺失 导致 T 细胞有丝分裂完全丧失 ，并且在 SAg 敏感的 HLA-DR4 转基因小鼠血流感染期间， 中 SElW 的表达增加了肝脏中的细菌载量。总体而言，我们报告了一种新型、高度流行且有效的 SAg 的特征，该 SAg 导致 感染的发病机制。 是一种与包括致命性坏死性肺炎和感染性心内膜炎在内的多种疾病相关的重要人类和动物病原体。 作为病原体的成功在一定程度上与其通过分泌毒素和免疫逃避分子来操纵宿主免疫反应的能力有关。葡萄球菌超抗原（SAg）已研究了数十年，但它们在 发病机制中的作用尚不清楚，对 SAg 如何操纵宿主免疫反应以促进感染的认识对于开发新的干预策略可能至关重要。在这里，我们鉴定了一种广泛存在的、以前隐匿的葡萄球菌 SAg，SElW，它有助于由 重要流行克隆 CC398 引起的 感染的严重程度。我们的发现增加了对葡萄球菌 SAg 多样性和功能的理解，并为 引起疾病的能力提供了新的见解。
