小鼠適應性SARS-CoV-2模型可用於測試COVID-19治療措施
作者：
小柯機器人發布時間：2020/8/28 22:59:19
美國北卡羅萊納大學教堂山分校Ralph S. Baric課題組建立一個小鼠適應性SARS-CoV-2模型，可用於測試COVID-19的治療措施。這一研究成果於2020年8月27日在線發表在《自然》上。
研究人員使用反向遺傳學重塑了突刺蛋白和小鼠ACE2（mACE2）之間的相互作用，從而產生了可以利用mACE2進入的重組病毒（SARS-CoV-2 MA）。SARS-CoV-2 MA在年輕成年小鼠和老年BALB/c小鼠的上呼吸道和下呼吸道均複製。重要的是，與HFH4-hACE2轉基因小鼠相比，老年小鼠的疾病更為嚴重，並且表現出更多的臨床相關表型。
然後，研究人員通過疫苗挑戰實驗在具有mACE2天然表達的強免疫力小鼠中證明了該模型的實用性。最後，研究人員表明臨床候選幹擾素（IFN）lambda-1a可以在體外有效抑制SARS-CoV-2在原代人氣道上皮細胞中的複製，並且預防性和治療性給藥均會減少小鼠中的複製。
這個小鼠適應性SARS-CoV-2模型證明了與年齡相關的疾病發病機理，並支持聚乙二醇化IFN lambda-1a治療在人COVID-19感染中的臨床應用。
據了解，SARS-CoV-2是COVID-19大流行的病原體，最近證明冠狀病毒容易出現在新的宿主物種中。目前迫切需要能夠概括SARS-CoV-2疾病的小型動物模型來快速評估醫學對策。由於病毒突刺S蛋白與人類受體ACE2的鼠直系同源物之間無有效相互作用，SARS-CoV-2無法感染野生型實驗小鼠。
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