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小鼠适应性SARS-CoV-2模型可用于测试COVID-19治疗措施
2020-08-28 22:59

美国北卡罗莱纳大学教堂山分校Ralph S. Baric课题组建立一个小鼠适应性SARS-CoV-2模型,可用于测试COVID-19的治疗措施。这一研究成果于2020年8月27日在线发表在《自然》上。

研究人员使用反向遗传学重塑了突刺蛋白和小鼠ACE2(mACE2)之间的相互作用,从而产生了可以利用mACE2进入的重组病毒(SARS-CoV-2 MA)。SARS-CoV-2 MA在年轻成年小鼠和老年BALB/c小鼠的上呼吸道和下呼吸道均复制。重要的是,与HFH4-hACE2转基因小鼠相比,老年小鼠的疾病更为严重,并且表现出更多的临床相关表型。
 
然后,研究人员通过疫苗挑战实验在具有mACE2天然表达的强免疫力小鼠中证明了该模型的实用性。最后,研究人员表明临床候选干扰素(IFN)lambda-1a可以在体外有效抑制SARS-CoV-2在原代人气道上皮细胞中的复制,并且预防性和治疗性给药均会减少小鼠中的复制。
 
这个小鼠适应性SARS-CoV-2模型证明了与年龄相关的疾病发病机理,并支持聚乙二醇化IFN lambda-1a治疗在人COVID-19感染中的临床应用。
 
据了解,SARS-CoV-2是COVID-19大流行的病原体,最近证明冠状病毒容易出现在新的宿主物种中。目前迫切需要能够概括SARS-CoV-2疾病的小型动物模型来快速评估医学对策。由于病毒突刺S蛋白与人类受体ACE2的鼠直系同源物之间无有效相互作用,SARS-CoV-2无法感染野生型实验小鼠。
 
附:英文原文

Title: A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Author: Kenneth H. Dinnon, Sarah R. Leist, Alexandra Schfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount, Yixuan J. Hou, Lily E. Adams, Kendra L. Gully, Ariane J. Brown, Emily Huang, Matthew D. Bryant, Ingrid C. Choong, Jeffrey S. Glenn, Lisa E. Gralinski, Timothy P. Sheahan, Ralph S. Baric

Issue&Volume: 2020-08-27

Abstract: Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs)2,3. 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, ACE24. We used reverse genetics5 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 infections6.

DOI: 10.1038/s41586-020-2708-8

Source: https://www.nature.com/articles/s41586-020-2708-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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