Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
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DOI：
10.1084/jem.20201241
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发表时间：
2020-12-01
影响因子：
15.3
通讯作者：
Iwasaki, Akiko
中科院分区：
文献类型：
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作者：
Israelow, Benjamin;Song, Eric;Iwasaki, Akiko
严重急性呼吸系统综合征-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。实验室小鼠一直是治疗和疫苗开发的中坚力量；然而，它们不支持SARS-CoV-2感染，因为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。虽然hACE2转基因小鼠支持感染和发病机制，但这些小鼠目前的可用性有限，并且仅限于单一遗传背景。在这里，我们报道了基于腺相关病毒（AAV）介导的hACE2表达的SARS-CoV-2小鼠模型的建立。这些小鼠支持病毒复制，并表现出在COVID-19患者中发现的病理结果。此外，我们发现I型干扰素不能控制体内SARS-CoV-2的复制，但却是病理反应的重要驱动因素。因此，AAV-hACE2小鼠模型能够在不同遗传背景的小鼠中使用真实的患者源性病毒进行SARS-CoV-2强感染后进行快速部署，以进行深入分析。
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.