Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.
J Exp Med. 2020 Dec 7;217(12). doi: 10.1084/jem.20201241.
Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）已导致超过 1300 万例冠状病毒病（COVID-19），死亡率很高。实验小鼠一直是治疗和疫苗开发的中坚力量；然而，由于该病毒无法使用其人类进入受体血管紧张素转换酶 2（hACE2）的小鼠同源物，它们不支持 SARS-CoV-2 的感染。虽然 hACE2 转基因小鼠支持感染和发病机制，但这些小鼠目前供应有限，仅限于单一遗传背景。在这里，我们报告了一种基于腺相关病毒（AAV）介导的 hACE2 表达的 SARS-CoV-2 小鼠模型的开发。这些小鼠支持病毒复制，并表现出 COVID-19 患者中发现的病理发现。此外，我们表明，I 型干扰素不能控制体内 SARS-CoV-2 的复制，但却是病理性反应的重要驱动因素。因此，AAV-hACE2 小鼠模型能够在具有不同遗传背景的小鼠中快速部署，以对源自真实患者的 SARS-CoV-2 进行深入分析。
