Abstract
The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.
Highlights
SARS-CoV-2 is a betacoronavirus and the causative agent of COVID-19, a febrile respiratory human disease that initially emerged in China in late 2019 and subsequently spread quickly worldwide [1, 2]
Of the keratin 18 promoter (K18)-human ACE2 (hACE2) mice in the high-dose challenge groups, all female mice and 80% of the male mice succumbed to disease
Virus RNA levels in lung, liver, and spleen were nearly identical between all the infected K18-hACE2 groups and remained high in most of the euthanized mice, apart from the mouse that died on day 11 (Figure 1, B and C, and Supplemental Figure 1C)
Summary
SARS-CoV-2 is a betacoronavirus and the causative agent of COVID-19, a febrile respiratory human disease that initially emerged in China in late 2019 and subsequently spread quickly worldwide [1, 2]. COVID-19 is primarily a respiratory disease with a wide spectrum of severity, ranging from a mild cough to the development of hypoxia, and in some cases resulting in a life-threatening acute respiratory distress syndrome requiring mechanical ventilation [3, 4]. SARS-CoV-2 human infections can cause vasculature damage and coagulopathies, leading to infarction [7,8,9]. Acute disease often presents with elevated levels of inflammatory cytokines, including IL-6, and these host molecules may play a role in the pathogenic process [10, 11]. Medical countermeasures (MCMs) are urgently needed to prevent this disease or to limit disease severity in a post exposure setting
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