小柯机器人

近日，美国德克萨斯大学Vineet D. Menachery及其团队发现，弗林蛋白酶切割位点的丧失能够减弱SARS-CoV-2的致病性。这一研究成果于2021年1月25日在线发表在国际学术期刊《自然》上。

研究人员表示，SARS-CoV-2是一种新型的冠状病毒（CoV），其突刺蛋白具有弗林蛋白酶切割位点（PRRAR），而其他2B型CoV则没有。

为了探索弗林蛋白酶切割位点是否有助于感染和发病，研究人员产生了缺失弗林蛋白酶切割位点（ΔPRRA）的突变SARS-CoV-2。与亲本SARS-CoV-2相比，SARS-CoV-2ΔPRRA具有更快的动力学，改善了Vero E6细胞的适应性并减少了刺突蛋白加工。但是，ΔPRRA突变体在人类呼吸细胞系中复制减少，并且在SARS-CoV-2发病的仓鼠和K18-hACE2转基因小鼠模型中均减弱。尽管疾病减少，但ΔPRRA突变体仍可保护其免受亲代SARS-CoV-2的攻击。

重要的是，COVID-19患者血清和受体结合域（RBD）单克隆抗体对ΔPRRA突变体的中和值相对于亲代SARS-CoV-2更低，这可能是由于颗粒/PFU比增加所致。总之，这些结果表明弗林蛋白酶切割位点在SARS-CoV-2感染中起关键作用，并突出了该位点在评估抗体中和活性中的重要性。 

附：英文原文

Title: Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis

Author: Bryan A. Johnson, Xuping Xie, Adam L. Bailey, Birte Kalveram, Kumari G. Lokugamage, Antonio Muruato, Jing Zou, Xianwen Zhang, Terry Juelich, Jennifer K. Smith, Lihong Zhang, Nathen Bopp, Craig Schindewolf, Michelle Vu, Abigail Vanderheiden, Emma S. Winkler, Daniele Swetnam, Jessica A. Plante, Patricia Aguilar, Kenneth S. Plante, Vsevolod Popov, Benhur Lee, Scott C. Weaver, Mehul S. Suthar, Andrew L. Routh, Ping Ren, Zhiqiang Ku, Zhiqiang An, Kari Debbink, Michael S. Diamond, Pei Yong Shi, Alexander N. Freiberg, Vineet D. Menachery

Issue&Volume: 2021-01-25

Abstract: SARS-CoV-2, a novel coronavirus (CoV)-producing worldwide pandemic1, has a furin cleavage site (PRRAR) in its spike protein that is absent in other group 2B CoVs2. To explore whether the furin cleavage site contributes to infection and pathogenesis, we generated a mutant SARS-CoV-2 deleting the furin cleavage site (ΔPRRA). SARS-CoV-2 ΔPRRA replicates had faster kinetics, improved fitness in Vero E6 cells, and reduced spike protein processing as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, COVID-19 patient sera and receptor-binding domain (RBD) monoclonal antibodies had lower neutralization values against the ΔPRRA mutant versus parental SARS-CoV-2, likely due to increased particle/PFU ratio. Together, these results demonstrate a critical role for the furin cleavage site in SARS-CoV-2 infection and highlight the importance of this site in evaluating antibody neutralization activity.

DOI: 10.1038/s41586-021-03237-4

Source: https://www.nature.com/articles/s41586-021-03237-4

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
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