Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

  1. Benjamin Israelow
  2. Eric Song
  3. Tianyang Mao
  4. Peiwen Lu
  5. Amit Meir
  6. Feimei Liu
  7. Mia Madel Alfajaro
  8. Jin Wei
  9. Huiping Dong
  10. Robert J. Homer
  11. Aaron Ring
  12. Craig B. Wilen
  13. Akiko Iwasaki

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Abstract

Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus’s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)–mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.

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  1. Version published to 10.1084/jem.20201241
  2. ScreenIT

    SciScore for 10.1101/2020.05.27.118893: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To assess the capacity for B6J AAV-hACE2 mice to mount an antibody response to SARS-CoV-2 challenge , we quantified anti spike protein IgG titers by ELISA9,10 .
    anti spike protein IgG
    suggested: None
    We found that while control infected mice did not develop anti-spike antibodies , AAV-hACE2 B6/J mice mounted a significant antibody response between 4- and 7- DPI , which continued to increase at 14 DPI ( Fig . 1h) .
    anti-spike
    suggested: None
    Next , to assess the neutralization potential of these antibodies , we performed plaque reduction neutralization assay ( PRNT ) using SARS-CoV-2 , and found PRNT75 at a serum dilution of 1:1024 as early as 7 DPI ( Fig 1i)
    SARS-CoV-2
    suggested: (Sino Biological Cat# 40143-R019, AB_2827973)
    Software and Algorithms
    SentencesResources
    Using the Interferome database ( http://www.interferome.org/) , we mapped the top upregulated genes to their transcriptional regulation by either type I , II , or III IFNs ( Fig . 2b) .
    http://www.interferome.org/
    suggested: (Interferome, SCR_007743)

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    About SciScore

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  3. Version published to 10.1101/2020.05.27.118893v1 on bioRxiv