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.
Highlights
The coronavirus disease 2019 (COVID-19) pandemic is caused by the recently identified β-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]
Intranasal inoculation, but not aerosol exposure, of SARS-CoV-2 leads to fatal neuroinvasion in K18-hACE2 transgenic mice
K18-hACE2 transgenic mice were infected with a target dose of 1 × 105 tissue culture infectious dose 50 (TCID50) of SARS-CoV-2 either through intranasal administration with 25 μl of diluted virus (IN) or through a 20 to 30 min exposure to aerosolized virus (AR) (Fig. 1A-B, see Methods)
Summary
The coronavirus disease 2019 (COVID-19) pandemic is caused by the recently identified β-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. CoV-2 and a direct role of CNS infection in the pathogenesis of neurological manifestations remains highly debated. The availability of tractable animal models to mechanistically dissect virological, immunological and pathogenetic aspects of the infection with SARS-CoV-2 and future human coronaviruses would provide major benefit. Wild-type laboratory mice are poorly susceptible to SARS-CoV-2 infection because the mouse angiotensin-converting enzyme (ACE) 2 does not act as a cellular receptor for the virus [13]. Several transgenic mouse lineages expressing the human version of the SARSCoV-2 receptor (hACE2) support viral replication and recapitulate certain clinical characteristics of the human infection [13]. The most widely used model is the K18-hACE2 transgenic mouse [14], which expresses hACE2 predominantly in
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