Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19

  1. Shelly J. Robertson
  2. Olivia Bedard
  3. Kristin L. McNally
  4. Carl Shaia
  5. Chad S. Clancy
  6. Matthew Lewis
  7. Rebecca M. Broeckel
  8. Abhilash I. Chiramel
  9. Jeffrey G. Shannon
  10. Gail L. Sturdevant
  11. Rebecca Rosenke
  12. Sarah L. Anzick
  13. Elvira Forte
  14. Christoph Preuss
  15. Candice N. Baker
  16. Jeffrey M. Harder
  17. Catherine Brunton
  18. Steven Munger
  19. Daniel P. Bruno
  20. Justin B. Lack
  21. Jacqueline M. Leung
  22. Amirhossein Shamsaddini
  23. Paul Gardina
  24. Daniel E. Sturdevant
  25. Jian Sun
  26. Craig Martens
  27. Steven M. Holland
  28. Nadia A. Rosenthal
  29. Sonja M. Best

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.

Article activity feed

  1. Version published to 10.1038/s41467-023-40076-5
  2. Version published to 10.1101/2021.09.17.460664v3 on bioRxiv
  3. Version published to 10.1101/2021.09.17.460664v2 on bioRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.09.17.460664: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Ethics statement: Animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at Rocky Mountain Laboratories (RML), NIAID, NIH in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH.
    Euthanasia Agents: Prior to inoculation mice were anesthetized by inhalation of isoflurane.
    Sex as a biological variableSix to 12 week-old male and female mice were inoculated by the intranasal route with 103 pfu of SARS-CoV-2 in a volume of 50ul PBS (Gibco).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationAuthentication: Multiplex cytokine/chemokine analysis: Sera were collected from SARS-CoV-2-infected mice at 3 and 6 dpi by centrifugation of whole blood in GelZ serum separation tubes (Sarstedt).

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Ten-fold serial dilutions of homogenates were prepared in duplicate and used to inoculate Vero cells grown in 48-well tissue culture plates.
    Vero
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mice and virus infection: CC founder x C57BL/6J -K18-hACE2 F1 were provided by The Jackson Laboratories and include the following: B6.Cg-Tg (K18-ACE2)2PrImn/J), 034860; (A/J x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035940; (PWK/PhJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035938; (NZO/HlLtJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035936; (129S1/SvImJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035934;
    C57BL/6J -K18-hACE2 F1
    suggested: None
    B6.Cg-Tg ( K18-ACE2)2PrImn/J
    suggested: None
    A/J x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    NZO/HlLtJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    129S1/SvImJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    (CAST/EiJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035937; (NOD/ShiLtJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035935; (WSB/EiJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035939; (BALB/cJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J, 035941; (BALB/cJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J 035943.
    CAST/EiJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    NOD/ShiLtJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    WSB/EiJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    BALB/cJ x B6.Cg-Tg(K18-ACE2)2Prlmn/J)F1/J
    suggested: None
    Samples were run in technical triplicate in 10ul reaction volumes on a 384-well plate, and mAce2 and hACE2 transcript abundance values were normalized to mGapdh in each sample and relative expression was calculated using a common reference lung sample (C57BL/6J male) and the delta delta-Ct method.
    C57BL/6J
    suggested: RRID:IMSR_JAX:000664)
    Software and Algorithms
    SentencesResources
    Samples were run on a Luminex Bio-Plex 200 system with BioPlex Manager 6.1.1 software.
    BioPlex
    suggested: (BioPlex, RRID:SCR_016144)
    All statistical analyses were performed with graphPad Prism 8.0 (GraphPad Software) or Qlucore Omics Explorer Version 3.7 (Qlucore AB).
    graphPad
    suggested: (GraphPad, RRID:SCR_000306)

    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

    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.

  5. Version published to 10.1101/2021.09.17.460664v1 on bioRxiv