Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant

  1. Zhen Cui
  2. Pan Liu
  3. Nan Wang
  4. Lei Wang
  5. Kaiyue Fan
  6. Qianhui Zhu
  7. Kang Wang
  8. Ruihong Chen
  9. Rui Feng
  10. Zijing Jia
  11. Minnan Yang
  12. Ge Xu
  13. Boling Zhu
  14. Wangjun Fu
  15. Tianming Chu
  16. Leilei Feng
  17. Yide Wang
  18. Xinran Pei
  19. Peng Yang
  20. Xiaoliang Sunney Xie
  21. Lei Cao
  22. Yunlong Cao
  23. Xiangxi Wang

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging new interactions that stably maintain an “active” conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Apart from already existing mutations, we have identified three new immune escape sites: 1) Q493R, 2) G446S and 3) S371L/S373P/S375F that confers greater resistance to five of the six classes of RBD-antibodies. Structure of the Omicron S bound with human ACE2, together with analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Article activity feed

  1. Version published to 10.1101/2021.12.29.474402v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2021.12.29.474402: (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

    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: HEK293T cells (ATCC, CRL-3216) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS).
    HEK293T
    suggested: None
    To obtain these proteins, the plasmids constructed above were transiently transfected into HEK293 F cells grown in suspension at 37°C in a rotating, humidified incubator supplied with 8% CO2 and maintained at 130 rpm.
    HEK293
    suggested: None
    Software and Algorithms
    SentencesResources
    Automated single particle data acquisition was carried out by SerialEM, with a calibrated magnification of 22,500 yielding a final pixel size of 1.07 A□.
    SerialEM
    suggested: (SerialEM, RRID:SCR_017293)
    All the micrographs were processed with MotionCor2 in Relion3.0.
    MotionCor2
    suggested: (MotionCor2, RRID:SCR_016499)
    The CTF value of each micrograph was estimated by Gctf.
    Gctf
    suggested: (GCTF, RRID:SCR_016500)
    When the potential conformation for the each structure was produced, particles from each candidate model were selected and processed by non-uniform auto-refinement and postprocessing in cryoSPARC to generate the final cryo-EM density for Delta S-trimer, Omicron S-trimer under neutral and acidic pH conditions and neutral Omicron S-trimer-hACE2 complex.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    Then the structure was manually adjusted and corrected according to the protein sequences and cryo-EM densities in Coot and finally real-space refinement was performing by Phenix.
    Coot
    suggested: (Coot, RRID:SCR_014222)
    Phenix
    suggested: (Phenix, RRID:SCR_014224)

    Results from OddPub: Thank you for sharing your data.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  3. Version published to 10.1101/2021.12.29.474402v1 on bioRxiv