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Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits

 Sung-Hee Kim  ;  Jiseon Kim  ;  Ji Yun Jang  ;  Hyuna Noh  ;  Jisun Park  ;  Haengdueng Jeong  ;  Donghun Jeon  ;  Chanyang Uhm  ;  Heeju Oh  ;  Kyungrae Cho  ;  Yoon Jeon  ;  Dain On  ;  Suhyeon Yoon  ;  Soo-Yeon Lim  ;  Sol Pin Kim  ;  Youn Woo Lee  ;  Hui Jeong Jang  ;  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  ;  Ho-Young Lee  ;  Kyoungmi Kim  ;  Daekee Lee  ;  Ho Lee  ;  Ki Taek Nam  ;  Je Kyung Seong 
 FRONTIERS IN IMMUNOLOGY, Vol.13 : 1055811, 2022-11 
Journal Title
Issue Date
Alveolar Epithelial Cells / virology ; Angiotensin-Converting Enzyme 2* / genetics ; Animals ; COVID-19* ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; SARS-CoV-2
K18-hACE2 mice model ; SARS-CoV-2 ; SCGB1A1-hACE2 mice model ; SFTPB-hACE2 mice model ; hACE2 transgenic mice
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung-Hee(김성희)
Nam, Ki Taek(남기택)
Park, Inho(박인호) ORCID logo https://orcid.org/0000-0003-2190-5469
Seo, Jun Young(서준영) ORCID logo https://orcid.org/0000-0003-4004-2013
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
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