Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design
Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design
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A 组链球菌 T 抗原具有隐藏在异质表面下的高度保守结构，这对疫苗设计具有重要意义
DOI：
10.1128/iai.00205-19
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发表时间：
2019
影响因子：
3.1
通讯作者：
N. Moreland
中科院分区：
文献类型：
--
作者：
P. Young;J. Raynes;J. Loh;T. Proft;E. Baker;N. Moreland
A组链球菌（GAS）（化脓性链球菌）是一种重要的人类病原体，与全球显著的发病率和死亡率相关，目前尚无安全有效的疫苗。T抗原是一种聚合形成GAS菌毛结构骨架的蛋白质，是一种潜在的候选疫苗。A组链球菌（GAS）（化脓性链球菌）是一种重要的人类病原体，与全球显著的发病率和死亡率相关，目前尚无安全有效的疫苗。T抗原是一种聚合形成GAS菌毛结构骨架的蛋白质，是一种潜在的候选疫苗。先前对编码T抗原的tee基因的调查已经鉴定了21种不同的tee类型和亚型，使得任何基于T抗原的疫苗必须是多价的并且被仔细设计以提供广泛的菌株覆盖。在这项研究中，晶体结构的三个两个结构域的T抗原（T3.2，T13，和T18.1）进行了测定，并发现有显着的结构相似性，以前报道的T1抗原，尽管适度的整体序列相似性。这使得所有主要的双结构域T抗原的可靠建模能够揭示T抗原序列变异沿着蛋白质的全长分布并屏蔽高度保守的核心。用来自免疫动物的血清和商业T型血清进行的免疫测定鉴定了T18.1、T18.2、T3.2和T13之间的显著交叉反应性抗体应答。T抗原之间共享表位的存在，结合显着保守的结构和高水平的表面序列差异，具有重要意义的设计多价T抗原为基础的疫苗。
Group A Streptococcus (GAS) (Streptococcus pyogenes) is an important human pathogen associated with significant global morbidity and mortality for which there is no safe and efficacious vaccine. The T antigen, a protein that polymerizes to form the backbone of the GAS pilus structure, is a potential vaccine candidate. ABSTRACT Group A Streptococcus (GAS) (Streptococcus pyogenes) is an important human pathogen associated with significant global morbidity and mortality for which there is no safe and efficacious vaccine. The T antigen, a protein that polymerizes to form the backbone of the GAS pilus structure, is a potential vaccine candidate. Previous surveys of the tee gene, which encodes the T antigen, have identified 21 different tee types and subtypes such that any T antigen-based vaccine must be multivalent and carefully designed to provide broad strain coverage. In this study, the crystal structures of three two-domain T antigens (T3.2, T13, and T18.1) were determined and found to have remarkable structural similarity to the previously reported T1 antigen, despite moderate overall sequence similarity. This has enabled reliable modeling of all major two-domain T antigens to reveal that T antigen sequence variation is distributed along the full length of the protein and shields a highly conserved core. Immunoassays performed with sera from immunized animals and commercial T-typing sera identified a significant cross-reactive antibody response between T18.1, T18.2, T3.2, and T13. The existence of shared epitopes between T antigens, combined with the remarkably conserved structure and high level of surface sequence divergence, has important implications for the design of multivalent T antigen-based vaccines.