Convergent structural features of respiratory syncytial virus neutralizing antibodies and plasticity of the site V epitope on prefusion F.
Convergent structural features of respiratory syncytial virus neutralizing antibodies and plasticity of the site V epitope on prefusion F.
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呼吸道合胞病毒中和抗体的趋同结构特征及预融合F上V位的可塑性。
DOI：
10.1371/journal.ppat.1008943
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发表时间：
2020-11
期刊：
影响因子：
6.7
通讯作者：
Chandramouli S
中科院分区：
文献类型：
--
作者：
Harshbarger W;Tian S;Wahome N;Balsaraf A;Bhattacharya D;Jiang D;Pandey R;Tungare K;Friedrich K;Mehzabeen N;Biancucci M;Chinchilla-Olszar D;Mallett CP;Huang Y;Wang Z;Bottomley MJ;Malito E;Chandramouli S
呼吸道合胞病毒（RSV）是一种全球公共卫生负担，目前还没有获得许可的疫苗。为了通过增加对RSV融合前糖蛋白F（PreF）的保护性抗体应答的理解来帮助疫苗开发，我们使用人中和抗体（nAb）RSB1进行了结构和功能研究。与RSB1复合的PreF的晶体结构揭示了具有独特的交叉原聚体结合机制的构象、融合前特异性位点V表位。我们确定了nAbs RSB1和CR9501之间共享的结构特征，首次阐明了从不同受试者获得的不同种系如何能够开发出趋同的分子机制，用于识别相同的PreF脆弱性位点。重要的是，RSB1样nAb诱导后，免疫与PreF在自然引发的牛。总之，这项工作揭示了位点V免疫原性的新细节，并进一步支持基于PreF的疫苗开发工作。呼吸道合胞病毒（RSV）是一种持久性、传染性的季节性病原体，严重威胁公共卫生。虽然婴儿是最危险的人群，感染可能导致细支气管炎，但成人，特别是老年人，也受到RSV引起的呼吸道感染的影响。目前针对RSV的唯一治疗方法是对高危婴儿进行被动免疫。因此，迫切需要为绝大多数没有预防性治疗的脆弱人群开发疫苗。RSV融合蛋白的融合前形式（PreF）是大多数天然诱导的中和抗体的靶点，目前有几项临床试验正在评估PreF作为一种有前途的候选疫苗。在这项研究中，我们解决了与人中和抗体的Fab片段结合的PreF的X射线结构。该结构揭示了可塑性的表位，以及一个独特的分子签名的抗体引起对该地区的PreF。我们还发现，类似的抗体诱导后，自然引发的牛与PreF疫苗抗原免疫，这表明该表位是高度免疫原性。这些结果将帮助我们更好地了解人类对RSV感染和疫苗接种的免疫反应，并指导未来的疫苗设计工作。
Respiratory syncytial virus (RSV) is a global public health burden for which no licensed vaccine exists. To aid vaccine development via increased understanding of the protective antibody response to RSV prefusion glycoprotein F (PreF), we performed structural and functional studies using the human neutralizing antibody (nAb) RSB1. The crystal structure of PreF complexed with RSB1 reveals a conformational, pre-fusion specific site V epitope with a unique cross-protomer binding mechanism. We identify shared structural features between nAbs RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same PreF site of vulnerability. Importantly, RSB1-like nAbs were induced upon immunization with PreF in naturally-primed cattle. Together, this work reveals new details underlying the immunogenicity of site V and further supports PreF-based vaccine development efforts. Respiratory syncytial virus (RSV) is a persistent, contagious seasonal pathogen and a serious public health threat. While infants are the most at-risk population, with infections potentially leading to bronchiolitis, adults, especially the elderly, are also burdened by RSV-induced respiratory infections. The only treatment currently available for RSV is passive immunization for high-risk infants. Thus, there is a critical need to develop a vaccine for the vast majority of the vulnerable population for which there is no preventative treatment. The RSV fusion protein in its prefusion form (PreF) is the target of the majority of naturally-induced neutralizing antibodies, and several clinical trials are currently evaluating PreF as a promising vaccine candidate. In this study, we solved the X-ray structure of PreF bound to the Fab fragment of a human neutralizing antibody. The structure reveals plasticity of the epitope, as well as a unique molecular signature for antibodies elicited towards this region of PreF. We also find that similar antibodies are induced upon immunization of naturally-primed cattle with a PreF vaccine antigen, suggesting that this epitope is highly immunogenic. These results will help us better understand the human immune response to RSV infection and vaccination, and guide future vaccine-design efforts.
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影响因子：
16.6
作者：
Gilman, Morgan S. A.;Furmanova-Hollenstein, Polina;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
0.1
作者：
Cartledge, Mark J.
通讯作者：
Cartledge, Mark J.
影响因子：
56.9
作者：
Crank, Michelle C.;Ruckwardt, Tracy J.;Graham, Barney S.
通讯作者：
Graham, Barney S.
影响因子：
5.5
作者：
Alford, Rebecca F.;Leaver-Fay, Andrew;Gray, Jeffrey J.
通讯作者：
Gray, Jeffrey J.