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

• DOI: 10.1126/sciimmunol.abl9929
• Publication Date: 2022-01-28T19:10:05Z
• Authors: 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-Ma...; Lorena Donnici; Lara Manganaro; Serena Delbue; Vania Broccoli; Raffaele De Franc...; Patrizia D’Adamo; Mirela Kuka; Luca G. Guidotti; Matteo Iannacone
• Keywords: Aerosolization; Respiratory tract; Pathogenesis; Coronavirus; Viral Pneumonia

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