Pilin Genotyping for Group A Streptococci

项目摘要 A组链球菌（GAS）是一种全球重要的人类病原体，主要感染喉咙 （咽炎）或皮肤（脓疱病），导致每年约7.5亿例感染;发病率和死亡率高 都是由侵袭性疾病和自身免疫并发症引起的尽管它作为全球病原体的重要性， 没有疫苗可用于预防GAS疾病。 全球GAS人群高度多样化，这在很大程度上是由于抗原的高度异质性。 在细胞表面蛋白中。多样性是通过广泛的水平基因转移放大的， 该物种产生许多独特的表面蛋白抗原组合。然而，一个生物学上相关的， 缺乏对GAS“应变”的标准化定义。历史上，两种血清学分型方案（M和T）被 用于表征GAS菌株：M-分型基于短M蛋白表面原纤维，T-分型基于 在细长的皮利上。除了高度的序列多样性外，M蛋白和皮利也是关键的毒力因子 是宿主保护性免疫的目标。emm基因分型已取代了m分型。拟议 项目寻求开发一种用于GAS皮利的基于序列的分型方案（即，T抗原）。 具体目标旨在开发一种基于粘附素和骨架菌毛蛋白基因的菌毛蛋白基因分型方案。 来自全球不同的GAS分离株的基因组序列是最初的来源材料。 菌毛蛋白基因的数据库;序列将进行系统发育分析和分配到簇。数据将 在www.pubmlst.org这一用户友好型网站上策划并公开提供。皮林型将结合 用emm类型和MLST定义的序列类型产生GAS“菌株”的定义。 拟议的工作将提供一个改进的分子流行病学分型方案，这一重大的全球 病原体命名的标准化可以促进GAS领域的“菌株”比较， 快速识别新出现的菌株。Pilin分型也将为今后的工作奠定基础， 新的假说，解决了不同类型的GAS疾病发病机制的分子基础， 新菌株出现和免疫逃逸的遗传基础。丰富的分子流行病学数据可以 还促进疫苗设计和疫苗接种战略的合理方法。在澄清 致病的分子机制和开发GAS疫苗是长期目标。

PROJECT SUMMARY Group A Streptococcus (GAS) is a human pathogen of global importance that primarily infects the throat (pharyngitis) or skin (impetigo), leading to ~750 million infections per year; high rates of morbidity and mortality are due to invasive disease and autoimmune complications. Despite its importance as a global pathogen, there is no vaccine available for the prevention of GAS disease. The global GAS population is highly diverse, due in large part to the high degree of antigenic heterogeneity among cell surface proteins. Diversity is amplified via the extensive horizontal gene transfer that characterizes this species to yield numerous unique combinations of surface protein antigens. Yet, a biologically relevant and standardized definition for GAS “strain” is lacking. Historically, two serological typing schemes (M and T) were used to characterize GAS strains: M-typing is based on the short M protein surface fibril, and T-typing is based on thin elongated pili. In addition to high sequence diversity, the M protein and pili act as key virulence factors and are targets of host protective immunity. M-typing has been supplanted by emm genotyping. The proposed project seeks to develop a sequence-based typing scheme for GAS pili (i.e., T-antigens). The Specific Aim seeks to develop a pilin genotyping scheme based on adhesin and backbone pilin genes. Genome sequences from a global and diverse collection of GAS isolates are the source material for the initial database of pilin genes; sequences will undergo phylogenetic analysis and assignment to clusters. Data will be curated and made publicly available on www.pubmlst.org, a user-friendly website. Pilin type will be combined with emm type and MLST-defined sequence type to yield a definition for GAS “strain.” The proposed work will provide an improved molecular epidemiology typing scheme for this major global pathogen. Standardization of nomenclature can facilitate “strain” comparisons in the GAS field and enable rapid recognition of newly emerged strains. Pilin typing will also provide a foundation for future work leading to new hypotheses that address the molecular basis for pathogenesis of different types of GAS disease, and the genetic basis for new strain emergence and immune escape. The enriched molecular epidemiology data can also promote rational approaches to vaccine design and vaccination strategies. Progress towards elucidating the molecular mechanisms of pathogenesis and developing a GAS vaccine are long-term goals.