Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants

  1. James W. Saville
  2. Dhiraj Mannar
  3. Xing Zhu
  4. Shanti S. Srivastava
  5. Alison M. Berezuk
  6. Jean-Philippe Demers
  7. Steven Zhou
  8. Katharine S. Tuttle
  9. Inna Sekirov
  10. Andrew Kim
  11. Wei Li
  12. Dimiter S. Dimitrov
  13. Sriram Subramaniam

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Abstract

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

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  1. Version published to 10.1038/s41467-022-28324-6
  2. ScreenIT

    SciScore for 10.1101/2021.09.02.458774: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Variant pseudotyped retroviral particles were produced in HEK293T cells as described previously49.
    HEK293T
    suggested: None
    Expi293 cells were transfected at a density of 3 × 10^6 cells/mL using linear polyethylenimine (Polysciences Cat# 23966-1).
    Expi293
    suggested: RRID:CVCL_D615)
    Recombinant DNA
    SentencesResources
    Antibodies: Recombinant proteins: Cell lines: Recombinant DNA and Oligonucleotides: Software and Algorithms: Pseudovirus Neutralization Assay: SARS-CoV-2 S protein Delta and Kappa genes were synthesized and inserted into pcDNA3.1 (
    pcDNA3.1
    suggested: RRID:Addgene_79663)
    Expression and Purification of Recombinant Spike Protein Constructs: The wild-type SARS-CoV-2 S HexaPro expression plasmid was previously described44 and was a gift from Jason McLellan (Addgene plasmid #154754; http://n2t.net/addgene:154754; RRID:Addgene_154754).
    detected: RRID:Addgene_154754)
    Software and Algorithms
    SentencesResources
    In general, all data processing was performed in cryoSPARC v.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    0.9.352, followed by iterative rounds of refinement in COOT and Phenix v.1.1953.
    Phenix
    suggested: (Phenix, RRID:SCR_014224)
    Glycans were added at N-linked glycosylation sites in COOT.
    COOT
    suggested: (Coot, RRID:SCR_014222)
    Figures were prepared using UCSF Chimera, UCSF ChimeraX v.1.1.155, and PyMOL (v.2.2 Schrodinger, LLC)
    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.

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

    About SciScore

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  3. Version published to 10.1101/2021.09.02.458774v1 on bioRxiv