SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

  1. Ferran Tarrés-Freixas
  2. Benjamin Trinité
  3. Anna Pons-Grífols
  4. Miguel Romero-Durana
  5. Eva Riveira-Muñoz
  6. Carlos Ávila-Nieto
  7. Mónica Pérez
  8. Edurne Garcia-Vidal
  9. Daniel Pérez-Zsolt
  10. Jordana Muñoz-Basagoiti
  11. Dàlia Raïch-Regué
  12. Nuria Izquierdo-Useros
  13. Ignacio Blanco
  14. Marc Noguera-Julián
  15. Victor Guallar
  16. Rosalba Lepore
  17. Alfonso Valencia
  18. Júlia Vergara-Alert
  19. Bonaventura Clotet
  20. Ester Ballana
  21. Jorge Carrillo
  22. Joaquim Segalés
  23. Julià Blanco

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Abstract

SARS-CoV-2 variants display enhanced transmissibility and/or immune evasion and can be generated in humans or animals, like minks, thus generating new reservoirs. The continuous surveillance of animal susceptibility to new variants is necessary to predict pandemic evolution. In this study we demonstrate that, compared to the B.1 SARS-CoV-2 variant, K18-hACE2 transgenic mice challenged with the B.1.351 variant displayed a faster progression of infection. Furthermore, we also report that B.1.351 can establish infection in wildtype mice, while B.1 cannot. B.1.351-challenged wildtype mice showed a milder infection than transgenic mice, confirmed by detectable viral loads in oropharyngeal swabs and tissues, lung pathology, immunohistochemistry and serology. In silico models supported these findings by demonstrating that the Spike mutations in B.1.351 resulted in increased affinity for both human and murine ACE2 receptors. Overall, this study highlights the plasticity of SARS-CoV-2 animal susceptibility landscape, which may contribute to viral persistence and expansion.

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    SciScore for 10.1101/2021.08.03.454861: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Animal Procedures and Study Design: All animal procedures were performed under the approval of the Committee on the Ethics of Animal Experimentation of the IGTP and the authorisation of Generalitat de Catalunya (code: 11222).
    Euthanasia Agents: Euthanasia was performed under deep isoflurane anaesthesia by whole blood extraction via cardiac puncture and was confirmed by cervical dislocation.
    Sex as a biological variableB6.Cg-Tg(K18-ACE2)2Prlmn/J (or K18-hACE2) hemizygous transgenic mice (034860; Jackson Immunoresearch, West Grove, PA, USA) were bred at CMCiB by pairing hemizygous males for Tg(K18-ACE2)2Prlmn (or K18-hACE2) with non-carrier B6.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Briefly, viruses were propagated in VeroE6 cells (CRL-1586; ATCC, Virginia, VA, USA) for two passages and recovered by supernatant collection.
    VeroE6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    B6.Cg-Tg(K18-ACE2)2Prlmn/J (or K18-hACE2) hemizygous transgenic mice (034860; Jackson Immunoresearch, West Grove, PA, USA) were bred at CMCiB by pairing hemizygous males for Tg(K18-ACE2)2Prlmn (or K18-hACE2) with non-carrier B6.
    B6.Cg-Tg(K18-ACE2)2Prlmn/J
    suggested: RRID:IMSR_JAX:034860)
    Recombinant DNA
    SentencesResources
    For absolute quantification, a standard curve was built using 1/5 serial dilutions of a SARS-CoV2 plasmid (2019-nCoV_N_Positive Control, catalog number 10006625, 200 copies/μL
    SARS-CoV2
    suggested: RRID:Addgene_153201)
    Software and Algorithms
    SentencesResources
    Biosafety Approval & Virus Isolation: The biologic biosafety committee of Germans Trias i Pujol Research Institute (IGTP) approved the execution of SARS-CoV-2 experiments at the BSL3 laboratory of the Centre for Bioimaging and Comparative Medicine (CMCiB, Badalona, Spain).
    Bioimaging
    suggested: None
    In a second step, using the MODELLER models as input, we ran FoldX v5 (Schymkowitz et al., 2005; Delgado et al., 2019) to model the mutations associated with the B.1.351 variant of the virus, obtaining 10 additional models (named mACE2-B.1.351 RBD) (Supplementary Fig. 3).
    MODELLER
    suggested: (MODELLER, RRID:SCR_008395)
    We evaluated each model with FoldX and pyDock (Cheng et al., 2007) which have achieved good performance predicting the impact of mutations in protein-protein complexes (Amengual-Rigo et al., 2021).
    FoldX
    suggested: (FoldX, RRID:SCR_008522)

    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.

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  2. Version published to 10.1101/2021.08.03.454861v1 on bioRxiv