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Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling.
bioRxiv - Immunology Pub Date : 2020-05-27 , DOI: 10.1101/2020.05.27.118893
Benjamin Israelow 1, 2 , Eric Song 1 , Tianyang Mao 1 , Peiwen Lu 1 , Amit Meir 3 , Feimei Liu 1 , Mia Madel Alfajaro 1, 4 , Jin Wei 1, 4 , Huiping Dong 1 , Robert J Homer 5 , Aaron Ring 1 , Craig B Wilen 1, 4 , Akiko Iwasaki 1, 6
Affiliation  

Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate. Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies. Laboratory mice have been the stalwart of these types of studies; however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog 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 antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models. Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses. Thus, the hACE2-AAV 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. This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19.

中文翻译:

SARS-CoV-2 小鼠模型揭示了 I 型干扰素信号传导的炎症作用。

严重急性呼吸系统综合症 - 冠状病毒 2 (SARS-Cov-2) 已导致超过 5,000,000 例冠状病毒病 (COVID-19) 病例,死亡率很高。由于这种全球大流行的紧迫性,许多治疗和疫苗试验已经开始,但没有进行惯常的安全性和有效性研究。实验室老鼠一直是这类研究的中坚力量。然而,由于其刺突 (S) 蛋白无法与其人类进入受体血管紧张素转换酶 2 (hACE2) 的小鼠直向同源物结合,因此它们不支持 SARS-CoV-2 感染。虽然 hACE2 转基因小鼠支持感染和发病机制,但这些小鼠目前的可用性有限,仅限于单一的遗传背景。在这里,我们报告了基于腺相关病毒 (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和抗体产生,并表现出在 COVID-19 患者和非人类灵长类动物模型中发现的病理结果。此外,我们表明 I 型干扰素无法控制 SARS-CoV2 复制和驱动病理反应。因此,hACE2-AAV 小鼠模型能够在具有不同遗传背景的小鼠中使用真实的患者源病毒感染 SARS-CoV-2 后进行快速部署,以进行深入分析。这是一个急需的平台,用于快速测试对抗 COVID-19 的预防和治疗策略。我们表明 I 型干扰素无法控制 SARS-CoV2 复制和驱动病理反应。因此,hACE2-AAV 小鼠模型能够在具有不同遗传背景的小鼠中使用真实的患者源病毒感染 SARS-CoV-2 后进行快速部署,以进行深入分析。这是一个急需的平台,用于快速测试对抗 COVID-19 的预防和治疗策略。我们表明 I 型干扰素无法控制 SARS-CoV2 复制和驱动病理反应。因此,hACE2-AAV 小鼠模型能够在具有不同遗传背景的小鼠中使用真实的患者源病毒感染 SARS-CoV-2 后进行快速部署,以进行深入分析。这是一个急需的平台,用于快速测试对抗 COVID-19 的预防和治疗策略。
更新日期:2020-05-27
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