SARS-CoV-2 and Three Related Coronaviruses Utilize Multiple ACE2 Orthologs and Are Potently Blocked by an Improved ACE2-Ig.
SARS-CoV-2 and Three Related Coronaviruses Utilize Multiple ACE2 Orthologs and Are Potently Blocked by an Improved ACE2-Ig.
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DOI：
10.1128/jvi.01283-20
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发表时间：
2020-10-27
影响因子：
5.4
通讯作者：
Zhong G
中科院分区：
文献类型：
--
作者：
Li Y;Wang H;Tang X;Fang S;Ma D;Du C;Wang Y;Pan H;Yao W;Zhang R;Zou X;Zheng J;Xu L;Farzan M;Zhong G
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是目前未受控制的2019冠状病毒病（COVID-19）大流行的病原体。研究SARS-CoV-2的宿主范围很重要，因为一些家养物种可能携带该病毒并将其传播回人类。此外，对SARS-CoV-2和SARS样病毒利用SARS-CoV-2受体ACE 2的动物直系同源物的能力的了解可能为改善基于ACE 2的病毒进入抑制剂提供结构上的了解。在这项研究中，我们发现广泛的家养和野生动物的ACE 2直系同源物可以支持SARS-CoV-2和三种相关冠状病毒进入细胞，为识别这些病毒的动物宿主提供了见解。我们还开发了能够有效阻断这些病毒感染的重组ACE 2-IG蛋白，为开发广泛有效对抗这些不同冠状病毒的抗病毒蛋白提供了一种有前途的方法。持续的2019冠状病毒病（COVID-19）大流行已造成超过2000万例感染和超过75万例死亡。严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）是COVID-19的病原体，已发现与蝙蝠冠状病毒菌株RaTG 13（Bat-CoV RaTG 13）和最近鉴定的穿山甲冠状病毒（Pangolin-CoV-2020）密切相关。在这里，我们首先研究了SARS-CoV-2和三种相关冠状病毒利用血管紧张素转换酶2（ACE 2）的动物直系同源物进入细胞的能力。我们发现，包括骆驼、牛、马、山羊、绵羊、猫、兔子和穿山甲在内的各种家养和野生哺乳动物的ACE 2直系同源物能够支持SARS-CoV-2进入细胞，这表明这些物种可能能够窝藏和传播这种病毒。此外，还发现穿山甲和蝙蝠冠状病毒Pangolin-CoV-2020和Bat-CoV RaTG 13能够利用人类ACE 2和许多动物ACE 2直系同源物进入细胞，这表明这些病毒未来有向人类传播的风险。然后，我们开发了有效的冠状病毒ACE 2-IG蛋白，其对四种不同的冠状病毒广泛有效。特别是，通过在其残基740处截短ACE 2而不是615处，引入D30 E突变，并采用抗体样四聚体-ACE 2构型，我们产生了ACE 2-IG变体，其在皮摩尔范围内中和SARS-CoV-2。这些数据表明，在这项研究中开发的改进的ACE 2-IG变体可能被开发用于保护SARS-CoV-2和其他一些可能在未来蔓延到人类的SARS样病毒。严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）是目前未受控制的2019冠状病毒病（COVID-19）大流行的病原体。研究SARS-CoV-2的宿主范围很重要，因为一些家养物种可能携带该病毒并将其传播回人类。此外，对SARS-CoV-2和SARS样病毒利用SARS-CoV-2受体ACE 2的动物直系同源物的能力的了解可能为改善基于ACE 2的病毒进入抑制剂提供结构上的了解。在这项研究中，我们发现广泛的家养和野生动物的ACE 2直系同源物可以支持SARS-CoV-2和三种相关冠状病毒进入细胞，为识别这些病毒的动物宿主提供了见解。我们还开发了能够有效阻断这些病毒感染的重组ACE 2-IG蛋白，为开发广泛有效对抗这些不同冠状病毒的抗病毒蛋白提供了一种有前途的方法。
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the currently uncontrolled coronavirus disease 2019 (COVID-19) pandemic. It is important to study the host range of SARS-CoV-2, because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. In this study, we found that ACE2 orthologs of a wide range of domestic and wild animals can support cell entry of SARS-CoV-2 and three related coronaviruses, providing insights into identifying animal hosts of these viruses. We also developed recombinant ACE2-Ig proteins that are able to potently block these viral infections, providing a promising approach to developing antiviral proteins broadly effective against these distinct coronaviruses. The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused >20 million infections and >750,000 deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, has been found closely related to the bat coronavirus strain RaTG13 (Bat-CoV RaTG13) and a recently identified pangolin coronavirus (Pangolin-CoV-2020). Here, we first investigated the ability of SARS-CoV-2 and three related coronaviruses to utilize animal orthologs of angiotensin-converting enzyme 2 (ACE2) for cell entry. We found that ACE2 orthologs of a wide range of domestic and wild mammals, including camels, cattle, horses, goats, sheep, cats, rabbits, and pangolins, were able to support cell entry of SARS-CoV-2, suggesting that these species might be able to harbor and spread this virus. In addition, the pangolin and bat coronaviruses, Pangolin-CoV-2020 and Bat-CoV RaTG13, were also found able to utilize human ACE2 and a number of animal-ACE2 orthologs for cell entry, indicating risks of spillover of these viruses into humans in the future. We then developed potently anticoronavirus ACE2-Ig proteins that are broadly effective against the four distinct coronaviruses. In particular, through truncating ACE2 at its residue 740 but not 615, introducing a D30E mutation, and adopting an antibody-like tetrameric-ACE2 configuration, we generated an ACE2-Ig variant that neutralizes SARS-CoV-2 at picomolar range. These data demonstrate that the improved ACE2-Ig variants developed in this study could potentially be developed to protect from SARS-CoV-2 and some other SARS-like viruses that might spillover into humans in the future. IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the currently uncontrolled coronavirus disease 2019 (COVID-19) pandemic. It is important to study the host range of SARS-CoV-2, because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. In this study, we found that ACE2 orthologs of a wide range of domestic and wild animals can support cell entry of SARS-CoV-2 and three related coronaviruses, providing insights into identifying animal hosts of these viruses. We also developed recombinant ACE2-Ig proteins that are able to potently block these viral infections, providing a promising approach to developing antiviral proteins broadly effective against these distinct coronaviruses.
具有输入约束的吸气式高超声速飞行器基于模糊逼近的规定性能控制
影响因子：
2.1
作者：
Li, Xingge;Li, Gang;Zhao, Yan;Kang, Xuchao
通讯作者：
Kang, Xuchao