Highly susceptible SARS-CoV-2 model in CAG promoter–driven hACE2-transgenic mice
Masamitsu N. Asaka, Daichi Utsumi, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, Yasuhiro Yasutomi
Masamitsu N. Asaka, Daichi Utsumi, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, Yasuhiro Yasutomi
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Resource and Technical Advance COVID-19

Highly susceptible SARS-CoV-2 model in CAG promoter–driven hACE2-transgenic mice

Abstract

COVID-19, caused by SARS-CoV-2, has spread worldwide with dire consequences. To urgently investigate the pathogenicity of COVID-19 and develop vaccines and therapeutics, animal models that are highly susceptible to SARS-CoV-2 infection are needed. In the present study, we established an animal model highly susceptible to SARS-CoV-2 via the intratracheal tract infection in CAG promoter–driven human angiotensin-converting enzyme 2–transgenic (CAG-hACE2) mice. The CAG-hACE2 mice showed several severe symptoms of SARS-CoV-2 infection, with definitive weight loss and subsequent death. Acute lung injury with elevated cytokine and chemokine levels was observed at an early stage of infection in CAG-hACE2 mice infected with SARS-CoV-2. Analysis of the hACE2 gene in CAG-hACE2 mice revealed that more than 15 copies of hACE2 genes were integrated in tandem into the mouse genome, supporting the high susceptibility to SARS-CoV-2. In the developed model, immunization with viral antigen or injection of plasma from immunized mice prevented body weight loss and lethality due to infection with SARS-CoV-2. These results indicate that a highly susceptible model of SARS-CoV-2 infection in CAG-hACE2 mice via the intratracheal tract is suitable for evaluating vaccines and therapeutic medicines.

Authors

Masamitsu N. Asaka, Daichi Utsumi, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, Yasuhiro Yasutomi

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Figure 7

Characterization of CAG-promoter hACE2-transgenic mice.

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Characterization of CAG-promoter hACE2-transgenic mice. (A) Chromosome m...
(A) Chromosome map of annotated hACE2-containing reads. The pink horizontal bars indicate the number of annotated ACE2-containing reads. Annotated site of integrated hACE2 is indicated as a blue box. (B) Detail of annotated site in chromosome 1. The horizontal red and pink bars indicate the ACE2-containing reads mapped to the plus and minus strand of the mouse reference genome (GRCh38/mm10), respectively. The blue box represents the duplicated region. (C) Schematic diagrams and sequences are shown as the hACE2-integrated site inside the first intron region of the Colgalt2 gene locus. The blue boxes denote duplicated regions. Each yellow arrow indicates the entire hACE2 sequence. Consensus sequences of reads at 5′- and 3′-junction sites are shown.