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Science immunology
Jan 28, 2022;7 (67): eabl9929.

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

Valeria Fumagalli, Micol Ravà, Davide Marotta, Pietro Di Lucia, Chiara Laura, Eleonora Sala, Marta Grillo, Elisa Bono, Leonardo Giustini, Chiara Perucchini, Marta Mainetti, Alessandro Sessa, José M Garcia-Manteiga, Lorena Donnici, Lara Manganaro, Serena Delbue, Vania Broccoli, Raffaele De Francesco, Patrizia D'Adamo, Mirela Kuka, Luca G Guidotti, Matteo Iannacone
Author Information
  1. Valeria Fumagalli: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  2. Micol Ravà: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  3. Davide Marotta: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  4. Pietro Di Lucia: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  5. Chiara Laura: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  6. Eleonora Sala: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  7. Marta Grillo: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  8. Elisa Bono: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  9. Leonardo Giustini: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  10. Chiara Perucchini: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  11. Marta Mainetti: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  12. Alessandro Sessa: Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  13. José M Garcia-Manteiga: Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  14. Lorena Donnici: INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Erica Invernizzi", Milan, Italy. ORCID
  15. Lara Manganaro: INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Erica Invernizzi", Milan, Italy.
  16. Serena Delbue: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy. ORCID
  17. Vania Broccoli: Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  18. Raffaele De Francesco: INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Erica Invernizzi", Milan, Italy. ORCID
  19. Patrizia D'Adamo: Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  20. Mirela Kuka: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  21. Luca G Guidotti: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
  22. Matteo Iannacone: Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. ORCID
PMID: 34812647 DOI: 10.1126/sciimmunol.abl9929

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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MeSH Term

Administration, Inhalation
Angiotensin-Converting Enzyme 2
Animals
COVID-19
Disease Models, Animal
Encephalitis, Viral
Epithelial Cells
Female
Humans
Keratin-18
Lung
Male
Mice
Mice, Transgenic
Nasal Sprays
Promoter Regions, Genetic
SARS-CoV-2
Transcriptome
Virus Replication

Chemicals

Keratin-18
Nasal Sprays
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000391 (Controlled administration of aerosolized SARS-CoV-2 to K18-hACE2 transgenic mice uncouples respiratory infection and anosmia from fatal neuroinvasion)

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