The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development
Animal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). I...
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Taylor & Francis Group
2024-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2024.2353302 |
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| author | Zhen Zhang Li Zhou Qianyun Liu Yucheng Zheng Xue Tan Zhixiang Huang Ming Guo Xin Wang Xianying Chen Simeng Liang Wenkang Li Kun Song Kun Yan Jiali Li Qiaohong Li Yuzhen Zhang Shimin Yang Zeng Cai Ming Dai Qiaoyang Xian Zheng-Li Shi Ke Xu Ke Lan Yu Chen |
| author_facet | Zhen Zhang Li Zhou Qianyun Liu Yucheng Zheng Xue Tan Zhixiang Huang Ming Guo Xin Wang Xianying Chen Simeng Liang Wenkang Li Kun Song Kun Yan Jiali Li Qiaohong Li Yuzhen Zhang Shimin Yang Zeng Cai Ming Dai Qiaoyang Xian Zheng-Li Shi Ke Xu Ke Lan Yu Chen |
| author_sort | Zhen Zhang |
| collection | DOAJ |
| description | Animal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR – Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development. |
| format | Article |
| id | doaj-art-fa17329035b44d72b792b36985b71803 |
| institution | OA Journals |
| issn | 2222-1751 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | Emerging Microbes and Infections |
| spelling | doaj-art-fa17329035b44d72b792b36985b718032025-08-20T02:21:03ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512024-12-0113110.1080/22221751.2024.2353302The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral developmentZhen Zhang0Li Zhou1Qianyun Liu2Yucheng Zheng3Xue Tan4Zhixiang Huang5Ming Guo6Xin Wang7Xianying Chen8Simeng Liang9Wenkang Li10Kun Song11Kun Yan12Jiali Li13Qiaohong Li14Yuzhen Zhang15Shimin Yang16Zeng Cai17Ming Dai18Qiaoyang Xian19Zheng-Li Shi20Ke Xu21Ke Lan22Yu Chen23State Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaInstitute for Vaccine Research, Animal Bio-Safety Level III Laboratory / Center for Animal Experiment, Wuhan University School of Medicine, Wuhan, People’s Republic of ChinaInstitute for Vaccine Research, Animal Bio-Safety Level III Laboratory / Center for Animal Experiment, Wuhan University School of Medicine, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, Modern Virology Research Center and RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, People’s Republic of ChinaAnimal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR – Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development.https://www.tandfonline.com/doi/10.1080/22221751.2024.2353302SARS-CoV-2mouse modelK18-hACE2 knock-in mousesevere pneumoniaOmicronantivirals |
| spellingShingle | Zhen Zhang Li Zhou Qianyun Liu Yucheng Zheng Xue Tan Zhixiang Huang Ming Guo Xin Wang Xianying Chen Simeng Liang Wenkang Li Kun Song Kun Yan Jiali Li Qiaohong Li Yuzhen Zhang Shimin Yang Zeng Cai Ming Dai Qiaoyang Xian Zheng-Li Shi Ke Xu Ke Lan Yu Chen The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development Emerging Microbes and Infections SARS-CoV-2 mouse model K18-hACE2 knock-in mouse severe pneumonia Omicron antivirals |
| title | The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development |
| title_full | The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development |
| title_fullStr | The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development |
| title_full_unstemmed | The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development |
| title_short | The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development |
| title_sort | lethal k18 hace2 knock in mouse model mimicking the severe pneumonia of covid 19 is practicable for antiviral development |
| topic | SARS-CoV-2 mouse model K18-hACE2 knock-in mouse severe pneumonia Omicron antivirals |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2024.2353302 |
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