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

The development of tractable animal models that faithfully reproduce COVID-19 pathogenesis would arguably be a major benefit. Infection of transgenic mice expressing the human version of the SARS-CoV-2 receptor (hACE2) by intranasal instillation of a liquid SARS-CoV-2 suspension under deep anesthesia results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the characterization of a novel COVID-19 mouse model based on an inhalation tower system that allows to expose 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 to 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 humans. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions. Bulk RNA-seq of lung homogenates 6 days after SARS-CoV-2 infection. Comparison between intranasal- (n=3) and aerosol- (n=4) infected mice, 2 PBS-treated mice are added as control