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 SeoJeong 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number1055811
JournalFrontiers in Immunology
Volume13
DOIs
StatePublished - 15 Nov 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Kim, Kim, Jang, Noh, Park, Jeong, Jeon, Uhm, Oh, Cho, Jeon, On, Yoon, Lim, Kim, Lee, Jang, Park, Oh, Seo, Kim, Seok, Lee, Hong, An, Kim, Kim, Hwang, Lee, Kim, Choi, Park, Seo, Yun, Shin, Lee, Kim, Lee, Lee, Nam and Seong.

Keywords

  • K18-hACE2 mice model
  • SARS-CoV-2
  • SCGB1A1-hACE2 mice model
  • SFTPB-hACE2 mice model
  • hACE2 transgenic mice

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