SARS-Cov-2-, HIV-1-, Ebola-neutralizing and anti-PD1 clones are predisposed

  1. Yanfang Zhang
  2. Qingxian Xu
  3. Huikun Zeng
  4. Minhui Wang
  5. Yanxia Zhang
  6. Chunhong Lan
  7. Xiujia Yang
  8. Yan Zhu
  9. Yuan Chen
  10. Qilong Wang
  11. Haipei Tang
  12. Yan Zhang
  13. Jiaqi Wu
  14. Chengrui Wang
  15. Wenxi Xie
  16. Cuiyu Ma
  17. Junjie Guan
  18. Shixin Guo
  19. Sen Chen
  20. Changqing Chang
  21. Wei Yang
  22. Lai Wei
  23. Jian Ren
  24. Xueqing Yu
  25. Zhenhai Zhang

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Abstract

Antibody repertoire refers to the totality of the superbly diversified antibodies within an individual to cope with the vast array of possible pathogens. Despite this extreme diversity, antibodies of the same clonotype, namely public clones, have been discovered among individuals. Although some public clones could be explained by antibody convergence, public clones in naïve repertoire or virus-neutralizing clones from not infected people were also discovered. All these findings indicated that public clones might not occur by random and they might exert essential functions. However, the frequencies and functions of public clones in a population have never been studied. Here, we integrated 2,449 Rep-seq datasets from 767 donors and discovered 5.07 million public clones – ~10% of the repertoire are public in population. We found 38 therapeutic clones out of 3,390 annotated public clones including anti-PD1 clones in healthy people. Moreover, we also revealed clones neutralizing SARS-CoV-2, Ebola, and HIV-1 viruses in healthy individuals. Our result demonstrated that these clones are predisposed in the human antibody repertoire and may exert critical functions during particular immunological stimuli and consequently benefit the donors. We also implemented RAPID – a R ep-seq A nalysis P latform with I ntegrated D atabases, which may serve as a useful tool for others in the field.

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    SciScore for 10.1101/2020.08.13.249086: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    Resources of known antibody: Five open access antibody databases, named abYsis (http://abysis.org/)48, bNAber (http://bnaber.org/)41, EMBLIG (http://acrmwww.biochem.ucl.ac.uk/abs/abybank/emblig/), HIV Molecular Immunology Database (HIV-DB: https://www.hiv.lanl.gov/content/immunology/neutralizing_ab_resources.html)49 and IMGT/LIGM-DB (http://www.imgt.org/ligmdb/)50 were enrolled.
    IMGT/LIGM-DB
    suggested: None
    Multiple sequence alignment for anti PD-1 antibodies: Variable region sequences with the same CDR3aa of Camrelizumab were extracted from each sample and grouped according to the VJ recombination and CDR3nt.
    anti PD-1
    suggested: None
    Construction of phylogenetic tree: Each phylogenetic tree was generated by the nucleotide sequences of variable regions for antibodies sharing the same CDR3 sequence with MT658807, MT658819, 1-20, MK901823, and KU760937.
    KU760937
    suggested: None
    Software and Algorithms
    SentencesResources
    Resources of known antibody: Five open access antibody databases, named abYsis (http://abysis.org/)48, bNAber (http://bnaber.org/)41, EMBLIG (http://acrmwww.biochem.ucl.ac.uk/abs/abybank/emblig/), HIV Molecular Immunology Database (HIV-DB: https://www.hiv.lanl.gov/content/immunology/neutralizing_ab_resources.html)49 and IMGT/LIGM-DB (http://www.imgt.org/ligmdb/)50 were enrolled.
    abYsis
    suggested: (Abysis Database, RRID:SCR_000756)
    After that, sequences were aligned to V, D, and J germline reference (downloaded from IMGT: http://www.imgt.org/ and listed in Supplementary Table 2) by IgBLAST24 (version 1.8.0), as its great performance for error-corrected reads23.
    IMGT
    suggested: (IMGT/HLA, RRID:SCR_002971)
    http://www.imgt.org/
    suggested: (IMGT - the international ImMunoGeneTics information system, RRID:SCR_012780)
    Based on results of IgBLAST, sequences which meet criteria were reserved, including in-frame, productive, with V, J, and CDR3, without either stop codon or out-of-frame in variable region, and without ambiguous base (N) in CDR3.
    IgBLAST
    suggested: (IgBLAST, RRID:SCR_002873)
    These keywords were selected from descriptions of the antibody sequences are stored in the database of abYsis, bNAber, HIV-DB, EMBLIG, and IMGT/LIGM-DB.
    IMGT/LIGM-DB
    suggested: None
    For sequences whose FR1 to FR4 regions were not completely reported by MiXCR, we extracted them using our algorithm: I) Reads which can not be merged by MiXCR were discarded; II) The beginning of variable region was acquired by pairwise alignment between germline reference of V genes and the column named “targetSequence” reported by MiXCR(The function pairwise2.align.localms from Python Bio module was used with parameters 2, −3, −5, and −2); III) If the column named “refPoints” in MiXCR recorded the region of FR4, we would use it instead of aligning “targetSequence” to J gene to find the end of FR4.
    Python
    suggested: (IPython, RRID:SCR_001658)
    Amino acid sequences of groups with most reads in each individual were used for multiple sequence alignment by Clustal W 2.1 with default parameters and visualized by BioEdit.
    BioEdit
    suggested: (BioEdit, RRID:SCR_007361)
    Alignments were performed using Clustal W 2.1, and the maximum parsimony trees fitted using DNAMLK by PHYLIP 3.69854.
    PHYLIP
    suggested: (PHYLIP, RRID:SCR_006244)
    Then PyMOL was used to calculate RMSD to compare the similarity of antibody structures.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.08.13.249086 on bioRxiv