Differential Pathogenesis of SARS-CoV-2 Variants of Concern in Human ACE2-Expressing Mice

  1. Janhavi Prasad Natekar
  2. Heather Pathak
  3. Shannon Stone
  4. Pratima Kumari
  5. Shaligram Sharma
  6. Tabassum Tasnim Auroni
  7. Komal Arora
  8. Hussin Alwan Rothan
  9. Mukesh Kumar

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current pandemic, resulting in millions of deaths worldwide. Increasingly contagious variants of concern (VoC) have fueled recurring global infection waves. A major question is the relative severity of the disease caused by previous and currently circulating variants of SARS-CoV-2. In this study, we evaluated the pathogenesis of SARS-CoV-2 variants in human ACE-2-expressing (K18-hACE2) mice. Eight-week-old K18-hACE2 mice were inoculated intranasally with a representative virus from the original B.1 lineage or from the emerging B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), or B.1.1.529 (omicron) lineages. We also infected a group of mice with the mouse-adapted SARS-CoV-2 (MA10). Our results demonstrate that B.1.1.7, B.1.351 and B.1.617.2 viruses are significantly more lethal than the B.1 strain in K18-hACE2 mice. Infection with the B.1.1.7, B.1.351, and B.1.617.2 variants resulted in significantly higher virus titers in the lungs and brain of mice compared with the B.1 virus. Interestingly, mice infected with the B.1.1.529 variant exhibited less severe clinical signs and a high survival rate. We found that B.1.1.529 replication was significantly lower in the lungs and brain of infected mice in comparison with other VoC. The transcription levels of cytokines and chemokines in the lungs of B.1- and B.1.1.529-infected mice were significantly less when compared with those challenged with other VoC. Together, our data provide insights into the pathogenesis of previous and circulating SARS-CoV-2 VoC in mice.

Article activity feed

  1. Version published to 10.3390/v14061139
  2. ScreenIT

    SciScore for 10.1101/2022.04.04.486975: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The protocol was approved by the Georgia State University Institutional Animal Care and Use Committee (Protocol number A20044).
    Euthanasia Agents: In independent experi-ments, mice were inoculated with PBS (Mock) or SARS-CoV-2 intranasally, and on days 3 and 5-7 after infection, animals were anesthetized using isoflurane and perfused with cold PBS.
    Sex as a biological variableRoughly equal numbers of male and female mice were used.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    To titrate the infectious virus, tissue homogenates were 10-fold serially diluted with DMEM and applied to monolayered Vero E6 cells for 1 hour.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Experimental Models: Organisms/Strains
    SentencesResources
    Hemizygous K18-hACE2 mice (2B6.Cg-Tg (K18-ACE2)2Prlmn/J) were obtained from The Jackson Laboratory.
    K18-hACE2
    suggested: RRID:IMSR_GPT:T037657)
    Eight-week-old hemizygous K18-ACE2 mice were inoculated intranasally with PBS (mock) or 104 plaque-forming units (PFU) of SARS-CoV-2 as described previously [8,21,22].
    K18-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    Infectious virus titration by plaque assays: Tissues harvested from virus-inoculated animals were weighed and homogenized in a bullet blender (Next Advance, Averill Park, NY, USA) using stainless steel or zirconium beads, followed by centrifugation and titration.
    Tissues
    suggested: None
    Statistical Analysis: GraphPad Prism 8.0 was used to perform a Kaplan Meier log-rank test to compare survival curves.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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 10.1101/2022.04.04.486975 on bioRxiv