Frontiers in Immunology (Nov 2022)
Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits
- Sung-Hee Kim,
- Jiseon Kim,
- Ji Yun Jang,
- Ji Yun Jang,
- Hyuna Noh,
- Jisun Park,
- Haengdueng Jeong,
- Donghun Jeon,
- Chanyang Uhm,
- Heeju Oh,
- Kyungrae Cho,
- Yoon Jeon,
- Dain On,
- Dain On,
- Suhyeon Yoon,
- Soo-Yeon Lim,
- Sol Pin Kim,
- Youn Woo Lee,
- Hui Jeong Jang,
- In Ho Park,
- In Ho Park,
- Jooyeon Oh,
- Jung Seon Seo,
- Jeong Jin Kim,
- Sang-Hyuk Seok,
- Yu Jin Lee,
- Seung-Min Hong,
- Se-Hee An,
- Seo Yeon Kim,
- Young Been Kim,
- Ji-Yeon Hwang,
- Hyo-Jung Lee,
- Hong Bin Kim,
- Kang-Seuk Choi,
- Jun Won Park,
- Jun-Young Seo,
- Jun-Won Yun,
- Jeon-Soo Shin,
- Jeon-Soo Shin,
- Jeon-Soo Shin,
- Ho-Young Lee,
- Ho-Young Lee,
- Kyoungmi Kim,
- Daekee Lee,
- Ho Lee,
- Ho Lee,
- Ki Taek Nam,
- Je Kyung Seong,
- Je Kyung Seong,
- Je Kyung Seong,
- Je Kyung Seong
Affiliations
- Sung-Hee Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Jiseon Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Ji Yun Jang
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, South Korea
- Ji Yun Jang
- College of Pharmacy, Dongguk University, Seoul, South Korea
- Hyuna Noh
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Jisun Park
- Department of Life Science, Ewha Womans University, Seoul, South Korea
- Haengdueng Jeong
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Donghun Jeon
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Chanyang Uhm
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Heeju Oh
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Kyungrae Cho
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Yoon Jeon
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, South Korea
- Dain On
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Dain On
- Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Suhyeon Yoon
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Soo-Yeon Lim
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Sol Pin Kim
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Youn Woo Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Hui Jeong Jang
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- In Ho Park
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- In Ho Park
- Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
- Jooyeon Oh
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
- Jung Seon Seo
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Jeong Jin Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Sang-Hyuk Seok
- 0Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, South Korea
- Yu Jin Lee
- 0Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, South Korea
- Seung-Min Hong
- 1Laboratory of Avian Diseases, BK21 plus Program for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Se-Hee An
- 1Laboratory of Avian Diseases, BK21 plus Program for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Seo Yeon Kim
- 2Preclinical Research Center, Seoul National University Bundang Hospital, Seongnam, South Korea
- Young Been Kim
- 2Preclinical Research Center, Seoul National University Bundang Hospital, Seongnam, South Korea
- Ji-Yeon Hwang
- 2Preclinical Research Center, Seoul National University Bundang Hospital, Seongnam, South Korea
- Hyo-Jung Lee
- 3Department of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam, South Korea
- Hong Bin Kim
- 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
- Kang-Seuk Choi
- 1Laboratory of Avian Diseases, BK21 plus Program for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Jun Won Park
- 0Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, South Korea
- Jun-Young Seo
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Jun-Won Yun
- 5Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Jeon-Soo Shin
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Jeon-Soo Shin
- Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
- Jeon-Soo Shin
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
- Ho-Young Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Ho-Young Lee
- 6Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, South Korea
- Kyoungmi Kim
- 7Department of Physiology and Biomedical Science, Korea University College of Medicine, Seoul, South Korea
- Daekee Lee
- Department of Life Science, Ewha Womans University, Seoul, South Korea
- Ho Lee
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, South Korea
- Ho Lee
- 8Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, South Korea
- Ki Taek Nam
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Je Kyung Seong
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
- Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Je Kyung Seong
- 9BIO-MAX Institute, Seoul National University, Seoul, South Korea
- Je Kyung Seong
- 0Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul, South Korea
- DOI
- https://doi.org/10.3389/fimmu.2022.1055811
- Journal volume & issue
-
Vol. 13
Abstract
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.
Keywords
- SARS-CoV-2
- hACE2 transgenic mice
- K18-hACE2 mice model
- SFTPB-hACE2 mice model
- SCGB1A1-hACE2 mice model
