A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.
A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.
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DOI：
10.1038/s41586-020-2708-8
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Baric RS
中科院分区：
文献类型：
--
作者：
Dinnon KH 3rd;Leist SR;Schäfer A;Edwards CE;Martinez DR;Montgomery SA;West A;Yount BL Jr;Hou YJ;Adams LE;Gully KL;Brown AJ;Huang E;Bryant MD;Choong IC;Glenn JS;Gralinski LE;Sheahan TP;Baric RS
冠状病毒容易出现新的宿主物种，最近的证明是SARS-CoV-2，COVID-19大流行的病原体。为了快速评估医学对策（MCMs），迫切需要重现SARS-CoV-2疾病的小动物模型。SARS-CoV-2不能感染野生型实验室小鼠，因为病毒刺突（S）蛋白和人类受体ACE 2的小鼠直系同源物之间的相互作用效率低下。我们使用反向遗传学来重塑S和mACE 2之间的相互作用，从而产生可以利用mACE 2进入的重组病毒（SARS-CoV-2 MA）。SARS-CoV-2 MA在年轻成年和老年BALB/c小鼠的上气道和下气道中复制。重要的是，老年小鼠的疾病更严重，并且显示出比HFH 4-hACE 2转基因小鼠中观察到的更多临床相关表型。然后，我们通过在具有mACE 2天然表达的免疫活性小鼠中的疫苗攻击研究证明了该模型的实用性。最后，我们表明，临床候选干扰素（IFN）λ-1a可以有效地抑制SARS冠状病毒2复制在原代人气道上皮细胞在体外，预防性和治疗性管理减少复制小鼠。我们的小鼠适应SARS-CoV-2模型证明了年龄相关的疾病发病机制，并支持聚乙二醇化IFN lambda-1a治疗人类COVID-19感染的临床用途。
Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the interaction between S and mACE2 resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in HFH4-hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN lambda-1a treatment in human COVID-19 infections.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
影响因子：
158.5
作者：
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影响因子：
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通讯作者：
Baric RS
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
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通讯作者：
Munster VJ
影响因子：
5.9
作者：
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通讯作者：
Glenn, Jeffrey S.