Highly susceptible SARS-CoV-2 model in CAG promoter–driven hACE2-transgenic mice
Masamitsu N. Asaka, … , Keiji Kuba, Yasuhiro Yasutomi
Masamitsu N. Asaka, … , Keiji Kuba, Yasuhiro Yasutomi
Published August 31, 2021
Citation Information: JCI Insight. 2021;6(19):e152529. https://doi.org/10.1172/jci.insight.152529.
View: Text | PDF
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

×

Figure 1

The pathogenesis of SARS-CoV-2 infection is exacerbated in a viral dose-dependent manner.

Options: View larger image (or click on image) Download as PowerPoint
The pathogenesis of SARS-CoV-2 infection is exacerbated in a viral dose-...
(A) Western blot of human ACE2 protein using various organs in WT and CAG-hACE2 mice. The top and bottom rows show hACE2 and GAPDH, respectively. (B) Schematic diagram of experimental schedule. Male and female C57BL/6 and CAG-hACE2 mice were infected via respiratory tract with SARS-CoV-2 (2 × 102 TCID50, n = 5; 2 × 103 TCID50, n = 6; 2 × 104 TCID50, n = 5) and were administrated with an equal volume of PBS for mock infection controls (WT, n = 3; CAG-hACE2 mice, n = 3). Body weight and survival were recorded daily for up to 14 days. (C and D) Percentage of initial body weight (C) and survival rate (D). Numbers in C represent the number of mice measured for body weight at each time. White and black circles indicate WT with mock infection and WT infected with 2 × 104 TCID50, respectively. Triangles denote CAG-hACE2 mice. White, orange, blue, and red triangles represent PBS, 2 × 102 TCID50, 2 × 103 TCID50, and 2 × 104 TCID50, respectively.