Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus–host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines Cxcl9 and Cxcl10, and genes associated with effector T-cell populations including Cd3 g, Cd8a, and Gzmb. Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine–cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.

概括冠状病毒疾病（COVID-19）一些特征的临床前小鼠模型将有助于集中研究发病机制和病毒-宿主反应。人血管紧张素转换酶 2 (hACE2) 作为严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的进入受体，通过与包膜刺突蛋白结合来感染人类。在此，我们报告了可快速部署的 COVID-19 小鼠模型的开发和表征。通过口咽递送表达 hACE2 的重组人 5 型腺病毒 (Ad5-hACE2) 来转导肺部表达 hACE2 的 C57BL/6J (B6) 小鼠。小鼠在转导后第 4 天感染 SARS-CoV-2，并出现与血管周围炎症相关的间质性肺炎，并且与 Ad5 空对照组相比，感染后第 3、6 和 12 天肺部病毒载量显着升高。在肺泡间隔的肺细胞中检测到 SARS-CoV-2。肺部转录组分析表明，受感染的 Ad5-hACE 小鼠的 IFN 依赖性趋化因子Cxcl9和Cxcl10以及与效应 T 细胞群相关的基因（包括 C d3 g、Cd8a 和 Gzmb）显着增加。通路分析显示，数据集中丰富了京都基因与基因组百科全书（KEGG）的多个通路，包括细胞因子-细胞因子受体相互作用、趋化因子信号通路、NOD样受体信号通路、麻疹通路和IL- 17 信号通路。这种反应与 COVID-19 患者肺部的临床反应相关。 这些结果表明，通过腺病毒传递系统表达 hACE2 使小鼠对 SARS-CoV-2 感染敏感，并导致轻微的 COVID-19 表型的发展，突出了宿主对 SARS-CoV-2 感染的免疫和炎症反应。这种可快速部署的 COVID-19 小鼠模型对于 COVID-19 的临床前和发病机制研究非常有用。