PDF(Pubmed)
Abstract：
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.
摘要：
COVID-19的动物模型有助于开发针对SARS-CoV-2的疫苗和抗病毒药物。抗病毒剂或疫苗的功效在具有不同程度疾病的不同动物模型中可能不同。这里,我们介绍了一个表达人血管紧张素转换酶2（ACE2）的小鼠模型。在这个模型中,通过CRISPR-Cas9(K18-hACE2KI)将具有人细胞角蛋白18启动子的ACE2敲入C57BL/6J小鼠的Hipp11基因座。鼻内接种高（3×105PFU）或低（2.5×102PFU）剂量的SARS-CoV-2野生型（WT），Delta,OmicronBA.1或OmicronBA.2变体，所有小鼠都表现出明显的感染症状,包括减肥,肺部病毒载量高，和间质性肺炎.在所有变体感染的K18-hACE2KI小鼠中观察到100％的致死率，延迟了Delta和BA.1的终点，并且观察到BA.2的致病性显着减弱。感染小鼠的肺炎伴随着中性粒细胞的浸润和肺纤维化。与K18-hACE2Tg小鼠和HFH4-hACE2Tg小鼠相比，K18-hACE2KI小鼠更容易感染SARS-CoV-2。在抗病毒药物测试中，REGN10933和Remdesivir在SARS-CoV-2感染的挑战下，K18-hACE2KI小鼠的抗病毒功效有限，而Nirmatrelvir,单克隆抗体4G4和mRNA疫苗有效保护小鼠免于死亡。我们的结果表明，K18-hACE2KI小鼠模型对SARS-CoV-2感染是致命且稳定的，并且对抗病毒开发是可行和严格的。
