严重急性呼吸系统综合征冠状病毒2型刺突免疫猕猴中和抗体谱系的多室多样化-动脉网

Multi-compartmental diversification of neutralizing antibody lineages dissected in SARS-CoV-2 spike-immunized macaques

Nature 等信源发布 2024-07-27 02:19

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AbstractThe continued evolution of SARS-CoV-2 underscores the need to understand qualitative aspects of the humoral immune response elicited by spike immunization. Here, we combine monoclonal antibody (mAb) isolation with deep B cell receptor (BCR) repertoire sequencing of rhesus macaques immunized with prefusion-stabilized spike glycoprotein.

。在这里，我们将单克隆抗体（mAb）分离与用融合前稳定的棘突糖蛋白免疫的恒河猴的深B细胞受体（BCR）库测序相结合。

Longitudinal tracing of spike-sorted B cell lineages in multiple immune compartments demonstrates increasing somatic hypermutation and broad dissemination of vaccine-elicited B cells in draining and non-draining lymphoid compartments, including the bone marrow, spleen and, most notably, periaortic lymph nodes.

在多个免疫区室中对尖峰分选的B细胞谱系的纵向追踪表明，在引流和非引流淋巴区室（包括骨髓，脾脏，最明显的是主动脉周围淋巴结）中，体细胞超突变增加，疫苗诱导的B细胞广泛传播。

Phylogenetic analysis of spike-specific monoclonal antibody lineages identified through deep repertoire sequencing delineates extensive intra-clonal diversification that shaped neutralizing activity. Structural analysis of the spike in complex with a broadly neutralizing mAb provides a molecular basis for the observed differences in neutralization breadth between clonally related antibodies.

通过深度库测序鉴定的穗特异性单克隆抗体谱系的系统发育分析描绘了形成中和活性的广泛克隆内多样化。具有广泛中和mAb的加标复合物的结构分析为观察到的克隆相关抗体之间中和宽度的差异提供了分子基础。

Our findings highlight that immunization leads to extensive intra-clonal B cell evolution where members of the same lineage can both retain the original epitope specificity and evolve to recognize additional spike variants not previously encountered..

我们的研究结果强调，免疫导致广泛的克隆内B细胞进化，其中同一谱系的成员既可以保留原始表位特异性，又可以进化为识别以前未遇到的其他尖峰变体。。

IntroductionHumoral immune responses against viral spike glycoproteins stimulated by infection or vaccination are characterized by polyclonal repertoires of antibodies that target distinct spike epitopes. Of these, a proportion mediates virus neutralization, and blocking viral entry into target cells.

引言针对感染或疫苗接种刺激的病毒刺突糖蛋白的体液免疫应答的特征在于靶向不同刺突表位的抗体的多克隆库。其中，一部分介导病毒中和，并阻止病毒进入靶细胞。

Viruses that cause chronic infections such as HIV-1, or globally persistent viruses such as Influenza virus, have evolved immune evasion strategies to circumvent host antibody responses, ensuring their continued transmission. Such escape mechanisms include sequence variations that abolish epitope recognition, as well as glycan and conformational shielding that limit access to functionally conserved epitopes targeted by broadly neutralizing antibodies1.During the SARS-CoV-2 pandemic, antibody escape mutations have increasingly evolved in the spike glycoprotein, curtailing population immunity established by previous infections and vaccinations2,3,4,5,6.

导致HIV-1等慢性感染的病毒或流感病毒等全球持久性病毒已经进化出免疫逃避策略，以规避宿主抗体反应，确保其持续传播。这种逃逸机制包括消除表位识别的序列变异，以及限制获得广泛中和抗体靶向的功能保守表位的聚糖和构象屏蔽1。在SARS-CoV-2大流行期间，抗体逃逸突变在棘突糖蛋白中越来越多地进化，削弱了先前感染和疫苗接种所建立的群体免疫力2,3,4,5,6。

All variants known to be currently circulating in humans are descendants of Omicron, carrying multiple immune escape mutations whose molecular basis is typically well understood7,8,9. Many such mutations were independently acquired in different sub-lineages through convergent evolution10.Following repeated or prolonged exposure to antigen, the host antibody response evolves via B cell diversification through somatic hypermutation (SHM) in germinal center (GC) reactions11,12.

目前已知在人类中传播的所有变体都是Omicron的后代，携带多种免疫逃逸突变，其分子基础通常被很好地理解7,8,9。许多这样的突变是通过趋同进化在不同的亚谱系中独立获得的10。在反复或长时间暴露于抗原后，宿主抗体反应通过生发中心（GC）反应中的体细胞超突变（SHM）通过B细胞多样化进化11,12。

Studies have shown that SHM-mediated affinity maturation of SARS-CoV-2 neutralizing antibodies can to some degree overcome immune escape13,14. How antigen-specific B cell lineages evolve following prime-boost immunizations with the ancestral D614G SARS-CoV-2 spike (lineage B.1), and how this influences the development of neutralization breadth, is of inte.

研究表明，SHM介导的SARS-CoV-2中和抗体的亲和力成熟可以在一定程度上克服免疫逃逸13,14。在用祖先D614G SARS-CoV-2尖峰（谱系B.1）进行初次增强免疫后，抗原特异性B细胞谱系如何进化，以及这如何影响中和广度的发展，是至关重要的。

Data availability

数据可用性

NGS repertoire sequencing data have been deposited in the European nucleotide archive (ENA) with the following accession numbers: from ERR12544449 to ERR12544478. Single-cell repertoire sequencing data have been deposited in the ENA with the following accession numbers: from OZ032182 to OZ034681. Monoclonal antibody sequences are deposited at GenBank with the following accession numbers: from PP208826 to PP208901.

NGS曲目测序数据已保存在欧洲核苷酸档案馆（ENA）中，登录号如下：从ERR12544449到ERR12544478。单细胞库测序数据已保存在ENA中，登录号如下：从OZ032182到OZ034681。单克隆抗体序列以以下登录号保藏在GenBank中：从PP208826到PP208901。

The associated accession numbers, coordinates and structure factors of the cryo-EM data reported in this paper are available from the Protein Data Bank (PDB) and the Electron Microscopy Data Bank (EMDB) under the accession codes PDB: 8Q5Y and 8P5M, and EMDB: EMD-18180, EMD-17451. Source data are provided in this paper..

本文报道的低温电磁数据的相关登录号，坐标和结构因子可从蛋白质数据库（PDB）和电子显微镜数据库（EMDB）获得，登录号为PDB:8Q5Y和8P5M，EMDB:EMD-18180，EMD-17451。本文提供了源数据。。

Code availability

代码可用性

IgDiscover22 v1.0.0 is available at https://gitlab.com/gkhlab/igdiscover22, Scripts used to generate all results in the paper are available at: https://gitlab.com/gkhlab/Multi-compartmental_diversification_of_neutralizing_antibody_lineages_dissected_in_SARS-CoV-2_spike-immunized_macaques and https://doi.org/10.5281/zenodo.11104687.

IGDiscovery22 v1.0.0可在https://gitlab.com/gkhlab/igdiscover22，用于生成论文中所有结果的脚本可从以下网站获得：https://gitlab.com/gkhlab/Multi-compartmental_diversification_of_neutralizing_antibody_lineages_dissected_in_SARS-CoV-2_spike-immunized_macaques和https://doi.org/10.5281/zenodo.11104687.

The HMM code for chimera identification is available at https://github.com/MurrellGroup/CHMMera..

嵌合体识别的HMM代码可在https://github.com/MurrellGroup/CHMMera..

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Schrödinger, L. L. C. The {PyMOL} Molecular Graphics System, Version ~1.8 (2015).Download referencesAcknowledgementsWe thank Dr. Bengt Eriksson and the personnel at the Astrid Fagraeus laboratory for expert assistance with animal experiments. We thank Novavax AB, Uppsala, Sweden, for the Matrix-M adjuvant.

Schrödinger，L.L.C.{PyMOL}分子图形系统，版本〜1.8（2015）。下载参考文献致谢我们感谢Bengt Eriksson博士和Astrid Fagraeus实验室的人员在动物实验方面提供的专家帮助。我们感谢瑞典乌普萨拉的Novavax AB提供Matrix-M佐剂。

All cryo-EM data were collected at the Karolinska Institutet’s 3D-EM facility. Analysis of 10X single-cell raw data was enabled, in part, by Anastasios Glaros and resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) at Uppmax, partially funded by the Swedish Research Council through grant agreements no.

。对10倍单细胞原始数据的分析部分由Anastasios Glaros和瑞典国家超级计算学术基础设施（NAISS）和Uppmax的瑞典国家计算基础设施（SNIC）提供的资源实现，部分资金由瑞典研究委员会通过第号赠款协议提供。

2022-06725 and no. 2018-05973. This project was supported by grants from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 101003653 (CoroNAb) to G.M.M., G.B.K.H., and B.M. from the Swedish Research Council to B.M. (2018-02381) and to G.B.K.H. (2017-00968), from SciLifeLab’s Pandemic Laboratory Preparedness program to B.M.

2022-06725和编号2018-05973。该项目得到了欧盟地平线2020研究与创新计划（Horizon 2020 research and innovation program）根据第101003653号资助协议（CoroNAb）向瑞典研究委员会（Swedish research Council）向通用汽车公司（G.M.M.）、通用汽车公司（G.B.K.H.）和通用汽车公司（B.M.）提供的资助，从SciLifeLab的大流行实验室准备计划到通用汽车公司（B.M.）（2018-02381）和通用汽车公司（G.B.K.H.）（2017-00968）。

(VC-2022-0028) and G.B.K.H. (VC-2022-0028), from the Erling Persson Foundation (20210125) to B.M. and G.B.K.H., from the he Swedish Research Council to B.M.H. (2017-6702 and 2018-3808) and the Knut and Alice Wallenberg Foundation to B.M.H. We also thank the Fondation Dormeur (Liechtenstein) for its generous contribution towards equipment.

（VC-2022-0028）和G.B.K.H.（VC-2022-0028），从二灵佩尔森基金会（20210125）到B.M.和G.B.K.H.，从瑞典研究委员会到B.M.H.（2017-6702和2018-3808），以及克努特和爱丽丝·沃伦伯格基金会到B.M.H。我们也感谢Dormeur基金会（列支敦士登）对设备的慷慨贡献。

Open access funding was provided by Karolinska Institutet.FundingOpen access funding provided by Karolinska Institute.Author informationAuthor notesThese authors contributed equally: Ben Murrell, Gunilla B. Karlsson Hedestam.Authors and AffiliationsDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, SwedenMarco Mandolesi, L.

开放获取资金由卡罗琳学院提供。资金由卡罗林斯卡研究所提供的开放获取资金。作者信息作者注意到这些作者做出了同样的贡献：Ben Murrell，Gunilla B.Karlsson Hedestam。作者和附属机构斯德哥尔摩卡罗林斯卡研究所微生物学，肿瘤和细胞生物学系，SwedenMarco Mandolesi，L。

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PubMed Google ScholarContributionsM.M., B.M., and G.B.K.H. designed the study, analyzed the results, and wrote the manuscript. L.H., C.K., S.K., and G.M. provided recombinant proteins. M.M. coordinated the NHP immunizations. M.M., X.C.D., and M.A. collected and processed the samples.

PubMed谷歌学术贡献。M、，B.M.和G.B.K.H.设计了这项研究，分析了结果，并撰写了手稿。五十、 H.，C.K.，S.K。和G.M.提供了重组蛋白。M、 M.协调NHP免疫接种。M、 M.，X.C.D.和M.A.收集并处理了样本。

B.M. and M.G. processed the single-cell raw data from 10x Chromium. M.M. generated the NGS libraries and performed lineage tracing and phylogenetic analysis. M.M. and M.C. performed the IG genotyping. M.Ch. implemented the FAD denoising method. A.S. and M.Ch. implemented the chimera detection method.

B、 M.和M.G.处理了10倍铬的单电池原始数据。M、 M.生成了NGS文库，并进行了谱系追踪和系统发育分析。M、 M.和M.C.进行了IG基因分型。M、 Ch.实现了FAD去噪方法。A、 S.和M.Ch.实施了嵌合体检测方法。

M.M., L.d.V., M.D., and S.K. cloned, expressed, and characterized mAbs. D.J.S., Y.Y., and J.F. performed neutralization studies. H.D. and B.M.H. Analyzed and solved the cryo-EM structures. M.M., H.D., G.B.K.H., and B.M. visualized the data. B.M., G.B.K.H., B.M.H., and G.M. acquired funding. All authors revised the manuscript and approved the final version prior to submission.Corresponding authorsCorrespondence to.

M、 M.，L.d.V.，M.d。和S.K.克隆，表达和表征单克隆抗体。D、 J.S.，Y.Y。和J.F.进行了中和研究。H、 D.和B.M.H.分析并解决了低温电磁结构。M、 M.，H.D.，G.B.K.H。和B.M.可视化了数据。B、 M.，G.B.K.H.，B.M.H。和G.M.获得了资金。。通讯作者通讯。

Marco Mandolesi or Gunilla B. Karlsson Hedestam.Ethics declarations

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Competing interests

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D.J.S. consults for AstraZeneca AB on matters related to monoclonal antibody therapeutics for Covid-19. The remaining authors declare no competing interests.

D、 J.S.为阿斯利康AB咨询与新型冠状病毒肺炎单克隆抗体治疗相关的事宜。其余作者声明没有利益冲突。

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Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleMandolesi, M., Das, H., de Vries, L. et al. Multi-compartmental diversification of neutralizing antibody lineages dissected in SARS-CoV-2 spike-immunized macaques.

转载和许可本文引用本文Mandolesi，M.，Das，H.，de Vries，L。等人。在SARS-CoV-2穗免疫猕猴中解剖的中和抗体谱系的多区室多样化。

Nat Commun 15, 6338 (2024). https://doi.org/10.1038/s41467-024-50286-0Download citationReceived: 15 February 2024Accepted: 03 July 2024Published: 27 July 2024DOI: https://doi.org/10.1038/s41467-024-50286-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》156338（2024）。https://doi.org/10.1038/s41467-024-50286-0Download引文接收日期：2024年2月15日接受日期：2024年7月3日发布日期：2024年7月27日OI：https://doi.org/10.1038/s41467-024-50286-0Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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