Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion

  1. Valeria Fumagalli
  2. Micol Ravà
  3. Davide Marotta
  4. Pietro Di Lucia
  5. Chiara Laura
  6. Eleonora Sala
  7. Marta Grillo
  8. Elisa Bono
  9. Leonardo Giustini
  10. Chiara Perucchini
  11. Marta Mainetti
  12. Alessandro Sessa
  13. José M. Garcia-Manteiga
  14. Lorena Donnici
  15. Lara Manganaro
  16. Serena Delbue
  17. Vania Broccoli
  18. Raffaele De Francesco
  19. Patrizia D’Adamo
  20. Mirela Kuka
  21. Luca G. Guidotti
  22. Matteo Iannacone

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Abstract

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2–infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.

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  1. Version published to 10.1126/sciimmunol.abl9929
  2. ScreenIT

    SciScore for 10.1101/2021.08.06.455382: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: All experimental animal procedures were approved by the Institutional Animal Committee of the San Raffaele Scientific Institute and all infectious work was performed in designed BSL-3 workspaces.
    Euthanasia Agents: Mice were euthanized by cervical dislocation.
    Sex as a biological variableSocial scent-discrimination test: The social scent-discrimination test was used to assess hyposmia/anosmia in IN- infected or AR-infected male mice compared to PBS-treated control male mice, as previously described (Zheng et al., 2021).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    In vivo …
  3. Version published to 10.1101/2021.08.06.455382v1 on bioRxiv