Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens.
Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens.
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呼吸道合胞病毒G免疫原的结构设计与抗原验证。
DOI：
10.1128/jvi.02201-21
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发表时间：
2022-04-13
影响因子：
5.4
通讯作者：
DuBois, Rebecca M.
中科院分区：
文献类型：
--
作者：
Castrejon, Ana M. Nunez;O'Rourke, Sara M.;Kauvar, Lawrence M.;DuBois, Rebecca M.
呼吸道合胞病毒（RSV）是儿童、老年人和免疫功能低下个体严重下呼吸道疾病的主要原因。目前，没有FDA批准的RSV疫苗。RSV G糖蛋白通过与人趋化因子受体CX3CR1相互作用用于病毒附着于宿主细胞并损害宿主免疫力。破坏这种相互作用的抗体对感染和疾病具有保护作用。然而，RSV G疫苗抗原的开发受到其低免疫原性和安全性问题的阻碍。先前的一项研究描述了三种含有单点突变的工程化RSV G蛋白，其诱导更高水平的IgG抗体，并且与野生型RSV G相比具有改善的安全性特征（H. C.作者声明：A. M. Nuñez Castrejon等人，Virus 13：352，2021，https：//doi.org/10.3390/v13020352）。然而，尚不清楚突变是否影响RSV G蛋白折叠和其构象表位的展示。在这项研究中，我们表明，RSV G S177 Q蛋白保留了高亲和力结合保护性的人类和小鼠单克隆抗体，并具有相同的反应性，作为野生型RSV G蛋白的人参考免疫球蛋白的RSV。此外，我们确定了与抗RSV G抗体3G12复合的RSV G S177 Q蛋白的高分辨率晶体结构，进一步验证了其抗原结构。这些研究首次表明，具有增加的免疫原性和安全性的工程化RSV G蛋白保留了高亲和力保护性抗体的构象表位，支持其作为RSV疫苗免疫原的进一步开发。呼吸道合胞病毒（RSV）可引起儿童、老年人和免疫功能低下人群的严重下呼吸道疾病。目前没有FDA批准的RSV疫苗。大多数疫苗开发工作都集中在RSV F蛋白上，并且该领域由于其不良的免疫原性和安全性问题而通常忽略了受体结合抗原RSV G。然而，先前已经鉴定了具有增加的免疫原性和安全性的单点突变RSV G蛋白。在这项研究中，我们研究了三种已知的RSV G突变蛋白的抗体反应性。我们发现，一个突变体RSV G蛋白保留高亲和力结合保护性单克隆抗体，是同样的人血清中的抗RSV抗体的认可，并形成相同的三维结构的野生型RSV G蛋白。我们的研究验证了RSV G蛋白作为RSV疫苗抗原的结构指导设计。
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of children, the elderly, and immunocompromised individuals. Currently, there are no FDA-approved RSV vaccines. The RSV G glycoprotein is used for viral attachment to host cells and impairment of host immunity by interacting with the human chemokine receptor CX3CR1. Antibodies that disrupt this interaction are protective against infection and disease. Nevertheless, development of an RSV G vaccine antigen has been hindered by its low immunogenicity and safety concerns. A previous study described three engineered RSV G proteins containing single-point mutations that induce higher levels of IgG antibodies and have improved safety profiles compared to wild-type RSV G (H. C. Bergeron, J. Murray, A. M. Nuñez Castrejon, et al., Viruses 13:352, 2021, https://doi.org/10.3390/v13020352). However, it is unclear if the mutations affect RSV G protein folding and display of its conformational epitopes. In this study, we show that the RSV G S177Q protein retains high-affinity binding to protective human and mouse monoclonal antibodies and has equal reactivity as wild-type RSV G protein to human reference immunoglobulin to RSV. Additionally, we determined the high-resolution crystal structure of RSV G S177Q protein in complex with the anti-RSV G antibody 3G12, further validating its antigenic structure. These studies show for the first time that an engineered RSV G protein with increased immunogenicity and safety retains conformational epitopes to high-affinity protective antibodies, supporting its further development as an RSV vaccine immunogen. IMPORTANCE Respiratory syncytial virus (RSV) causes severe lower respiratory diseases of children, the elderly, and immunocompromised populations. There currently are no FDA-approved RSV vaccines. Most vaccine development efforts have focused on the RSV F protein, and the field has generally overlooked the receptor-binding antigen RSV G due to its poor immunogenicity and safety concerns. However, single-point mutant RSV G proteins have been previously identified that have increased immunogenicity and safety. In this study, we investigate the antibody reactivities of three known RSV G mutant proteins. We show that one mutant RSV G protein retains high-affinity binding to protective monoclonal antibodies, is equally recognized by anti-RSV antibodies in human sera, and forms the same three-dimensional structure as the wild-type RSV G protein. Our study validates the structure-guided design of the RSV G protein as an RSV vaccine antigen.
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