tetano
Editor, Senior Moderator
Front Immunol
. 2022 Nov 15;13:1055811.
doi: 10.3389/fimmu.2022.1055811. eCollection 2022.
Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits
Sung-Hee Kim[SUP] 1 [/SUP], Jiseon Kim[SUP] 1 [/SUP], Ji Yun Jang[SUP] 2 3 [/SUP], Hyuna Noh[SUP] 4 [/SUP], Jisun Park[SUP] 5 [/SUP], Haengdueng Jeong[SUP] 1 [/SUP], Donghun Jeon[SUP] 1 [/SUP], Chanyang Uhm[SUP] 1 [/SUP], Heeju Oh[SUP] 1 [/SUP], Kyungrae Cho[SUP] 1 [/SUP], Yoon Jeon[SUP] 2 [/SUP], Dain On[SUP] 4 6 [/SUP], Suhyeon Yoon[SUP] 4 [/SUP], Soo-Yeon Lim[SUP] 4 [/SUP], Sol Pin Kim[SUP] 4 [/SUP], Youn Woo Lee[SUP] 7 [/SUP], Hui Jeong Jang[SUP] 7 [/SUP], In Ho Park[SUP] 1 8 [/SUP], Jooyeon Oh[SUP] 9 [/SUP], Jung Seon Seo[SUP] 1 [/SUP], Jeong Jin Kim[SUP] 1 [/SUP], Sang-Hyuk Seok[SUP] 10 [/SUP], Yu Jin Lee[SUP] 10 [/SUP], Seung-Min Hong[SUP] 11 [/SUP], Se-Hee An[SUP] 11 [/SUP], Seo Yeon Kim[SUP] 12 [/SUP], Young Been Kim[SUP] 12 [/SUP], Ji-Yeon Hwang[SUP] 12 [/SUP], Hyo-Jung Lee[SUP] 13 [/SUP], Hong Bin Kim[SUP] 14 [/SUP], Kang-Seuk Choi[SUP] 11 [/SUP], Jun Won Park[SUP] 10 [/SUP], Jun-Young Seo[SUP] 1 [/SUP], Jun-Won Yun[SUP] 15 [/SUP], Jeon-Soo Shin[SUP] 1 8 9 [/SUP], Ho-Young Lee[SUP] 7 16 [/SUP], Kyoungmi Kim[SUP] 17 [/SUP], Daekee Lee[SUP] 5 [/SUP], Ho Lee[SUP] 2 18 [/SUP], Ki Taek Nam[SUP] 1 [/SUP], Je Kyung Seong[SUP] 4 6 19 20 [/SUP]
Affiliations
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 ≥10[SUP]5[/SUP] 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 10[SUP]5[/SUP] 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: K18-hACE2 mice model; SARS-CoV-2; SCGB1A1-hACE2 mice model; SFTPB-hACE2 mice model; hACE2 transgenic mice.
. 2022 Nov 15;13:1055811.
doi: 10.3389/fimmu.2022.1055811. eCollection 2022.
Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits
Sung-Hee Kim[SUP] 1 [/SUP], Jiseon Kim[SUP] 1 [/SUP], Ji Yun Jang[SUP] 2 3 [/SUP], Hyuna Noh[SUP] 4 [/SUP], Jisun Park[SUP] 5 [/SUP], Haengdueng Jeong[SUP] 1 [/SUP], Donghun Jeon[SUP] 1 [/SUP], Chanyang Uhm[SUP] 1 [/SUP], Heeju Oh[SUP] 1 [/SUP], Kyungrae Cho[SUP] 1 [/SUP], Yoon Jeon[SUP] 2 [/SUP], Dain On[SUP] 4 6 [/SUP], Suhyeon Yoon[SUP] 4 [/SUP], Soo-Yeon Lim[SUP] 4 [/SUP], Sol Pin Kim[SUP] 4 [/SUP], Youn Woo Lee[SUP] 7 [/SUP], Hui Jeong Jang[SUP] 7 [/SUP], In Ho Park[SUP] 1 8 [/SUP], Jooyeon Oh[SUP] 9 [/SUP], Jung Seon Seo[SUP] 1 [/SUP], Jeong Jin Kim[SUP] 1 [/SUP], Sang-Hyuk Seok[SUP] 10 [/SUP], Yu Jin Lee[SUP] 10 [/SUP], Seung-Min Hong[SUP] 11 [/SUP], Se-Hee An[SUP] 11 [/SUP], Seo Yeon Kim[SUP] 12 [/SUP], Young Been Kim[SUP] 12 [/SUP], Ji-Yeon Hwang[SUP] 12 [/SUP], Hyo-Jung Lee[SUP] 13 [/SUP], Hong Bin Kim[SUP] 14 [/SUP], Kang-Seuk Choi[SUP] 11 [/SUP], Jun Won Park[SUP] 10 [/SUP], Jun-Young Seo[SUP] 1 [/SUP], Jun-Won Yun[SUP] 15 [/SUP], Jeon-Soo Shin[SUP] 1 8 9 [/SUP], Ho-Young Lee[SUP] 7 16 [/SUP], Kyoungmi Kim[SUP] 17 [/SUP], Daekee Lee[SUP] 5 [/SUP], Ho Lee[SUP] 2 18 [/SUP], Ki Taek Nam[SUP] 1 [/SUP], Je Kyung Seong[SUP] 4 6 19 20 [/SUP]
Affiliations
- PMID: 36457995
- PMCID: PMC9706212
- DOI: 10.3389/fimmu.2022.1055811
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 ≥10[SUP]5[/SUP] 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 10[SUP]5[/SUP] 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: K18-hACE2 mice model; SARS-CoV-2; SCGB1A1-hACE2 mice model; SFTPB-hACE2 mice model; hACE2 transgenic mice.