The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2024 |
| Předmět: | |
| Zdroj: | Emerging Microbes and Infections, Vol 13, Iss 1 (2024) |
| Druh dokumentu: | article |
| ISSN: | 22221751 2222-1751 17329035 |
| DOI: | 10.1080/22221751.2024.2353302 |
| Popis: | ABSTRACTAnimal 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. |
| Databáze: | Directory of Open Access Journals |
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