The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus

  1. Wenjuan Dong
  2. Heather Mead
  3. Lei Tian
  4. Jun-Gyu Park
  5. Juan I. Garcia
  6. Sierra Jaramillo
  7. Tasha Barr
  8. Daniel S. Kollath
  9. Vanessa K. Coyne
  10. Nathan E. Stone
  11. Ashley Jones
  12. Jianying Zhang
  13. Aimin Li
  14. Li-Shu Wang
  15. Martha Milanes-Yearsley
  16. Jordi B. Torrelles
  17. Luis Martinez-Sobrido
  18. Paul S. Keim
  19. Bridget Marie Barker
  20. Michael A. Caligiuri
  21. Jianhua Yu

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Abstract

The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases, caused nearly 5 million deaths worldwide as of October 2021, and has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed.

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  1. Version published to 10.1128/jvi.00964-21
  2. ScreenIT

    SciScore for 10.1101/2021.05.08.443244: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The animal protocol of these studies was reviewed and approved by the institutional animal care and use committee of Northern Arizona University (protocol #20-005).
    Sex as a biological variableMouse infection: Female and Male of six-to-eight-week-old K18-hACE2 transgenic mice under the C57BL/6J background were anesthetized and intranasally (i.n.) infected with SARS-COV-2 virus at a dosage of 2 × 101 PFU/mouse, 2 × 102 PFU/mouse, 2 × 103 PFU/mouse or 2 × 104 PFU/mouse.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    For single IHC stain, the primary antibodies were incubated with DISCOVERY anti-Rabbit HQ following by DISCOVERY anti-HQ-HRP incubation.
    anti-Rabbit
    suggested: None
    Following each primary antibody incubation, DISCOVERY anti-Rabbit HQ or NP or DISCOVERY anti-Mouse HQ or NP and DISCOVERY anti-HQ-HRP or anti-NP-AP were incubated.
    anti-Mouse HQ
    suggested: (Roche Cat# 760-700, RRID:AB_2833075)
    DISCOVERY
    suggested: None
    anti-HQ-HRP
    suggested: None
    anti-NP-AP
    suggested: None
    The following primary Antibody information were listed: SPIKE (40150-T62, Sino Biological, at 1:2000), NP (NB100-56576, NOVUS, 1/100), hACE2 (AMAB91262, SIGMA, at 1:1000), CC10 (SC-365992#, Santa Cruz at 1/5000), Pro-SPC (AB37386, Millipore at 1/500), CD68 (ab125212, abcam, at 1/100) and NeuN (24307, cell signaling, at 1/100).
    AMAB91262
    suggested: (Atlas Antibodies Cat# AMAb91262, RRID:AB_2665871)
    CC10
    suggested: (Santa Cruz Biotechnology Cat# sc-365992, RRID:AB_10915481)
    CD68
    suggested: (Abcam Cat# ab125212, RRID:AB_10975465)
    NeuN
    suggested: (Cell Signaling Technology Cat# 24307, RRID:AB_2651140)
    Experimental Models: Cell Lines
    SentencesResources
    The viruses were amplified using Vero-E6 cells (ATCC).
    Vero-E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    The K18-hACE2 transgenic mice, which use the human keratin 18 (KRT18) promoter to direct human ACE2 expression, were purchased from the Jackson Laboratory.
    K18-hACE2
    suggested: RRID:IMSR_GPT:T037657)
    Mouse infection: Female and Male of six-to-eight-week-old K18-hACE2 transgenic mice under the C57BL/6J background were anesthetized and intranasally (i.n.) infected with SARS-COV-2 virus at a dosage of 2 × 101 PFU/mouse, 2 × 102 PFU/mouse, 2 × 103 PFU/mouse or 2 × 104 PFU/mouse.
    C57BL/6J
    suggested: None
    Software and Algorithms
    SentencesResources
    The following primary Antibody information were listed: SPIKE (40150-T62, Sino Biological, at 1:2000), NP (NB100-56576, NOVUS, 1/100), hACE2 (AMAB91262, SIGMA, at 1:1000), CC10 (SC-365992#, Santa Cruz at 1/5000), Pro-SPC (AB37386, Millipore at 1/500), CD68 (ab125212, abcam, at 1/100) and NeuN (24307, cell signaling, at 1/100).
    SPIKE
    suggested: (SPIKE, RRID:SCR_010466)

    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.

  3. Version published to 10.1101/2021.05.08.443244v1 on bioRxiv