Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits.
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Kim Sung-Hee, Kim Jiseon, Jang Ji Yun, Noh Hyuna, Park Jisun, Jeong Haengdueng, Jeon Donghun, Uhm Chanyang, Oh Heeju, Cho Kyungrae, Jeon Yoon, On Dain, Yoon Suhyeon, Lim Soo-Yeon, Kim Sol Pin, Lee Youn Woo, Jang Hui Jeong, Park In Ho, Oh Jooyeon, Seo Jung Seon, Kim Jeong Jin, Seok Sang-Hyuk, Lee Yu Jin, Hong Seung-Min, An Se-Hee, Kim Seo Yeon, Kim Young Been, Hwang Ji-Yeon, Lee Hyo-Jung, Kim Hong Bin, Choi Kang-Seuk, Park Jun Won, Seo Jun-Young, Yun Jun-Won, Shin Jeon-Soo, Lee Ho-Young, Kim Kyoungmi, Lee Daekee, Lee Ho, Nam Ki Taek, Seong Je Kyung
Аннотация
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has been a global health concern since 2019. The viral spike protein infects the host by binding to angiotensin-converting enzyme 2 (ACE2) expressed on the cell surface, which is then processed by type II transmembrane serine protease. However, ACE2 does not react to SARS-CoV-2 in inbred wild-type mice, which poses a challenge for preclinical research with animal models, necessitating a human ACE2 (hACE2)-expressing transgenic mouse model. Cytokeratin 18 (K18) promoter-derived hACE2 transgenic mice [B6.Cg-Tg(K18-ACE2)2Prlmn/J] are widely used for research on SARS-CoV-1, MERS-CoV, and SARS-CoV-2. However, SARS-CoV-2 infection is lethal at ≥105 PFU and SARS-CoV-2 target cells are limited to type-1 alveolar pneumocytes in K18-hACE2 mice, making this model incompatible with infections in the human lung. Hence, we developed lung-specific SARS-CoV-2 infection mouse models with surfactant protein B (SFTPB) and secretoglobin family 1a member 1 (Scgb1a1) promoters. After inoculation of 105 PFU of SARS-CoV-2 to the K18-hACE2, SFTPB-hACE2, and SCGB1A1-hACE2 models, the peak viral titer was detected at 2 days post-infection and then gradually decreased. In K18-hACE2 mice, the body temperature decreased by approximately 10°C, body weight decreased by over 20%, and the survival rate was reduced. However, SFTPB-hACE2 and SCGB1A1-hACE2 mice showed minimal clinical signs after infection. The virus targeted type I pneumocytes in K18-hACE2 mice; type II pneumocytes in SFTPB-hACE2 mice; and club, goblet, and ciliated cells in SCGB1A1-hACE2 mice. A time-dependent increase in severe lung lesions was detected in K18-hACE2 mice, whereas mild lesions developed in SFTPB-hACE2 and SCGB1A1-hACE2 mice. Spleen, small intestine, and brain lesions developed in K18-hACE2 mice but not in SFTPB-hACE2 and SCGB1A1-hACE2 mice. These newly developed SFTPB-hACE2 and SCGB1A1-hACE2 mice should prove useful to expand research on hACE2-mediated respiratory viruses.