病毒学
蛋白酵素
单克隆抗体
生物
冠状病毒
中东呼吸综合征
表位
二肽基肽酶-4
中东呼吸综合征冠状病毒
抗体
中和抗体
病毒进入
病毒
病毒复制
免疫学
医学
2019年冠状病毒病(COVID-19)
酶
传染病(医学专业)
病理
糖尿病
2型糖尿病
内分泌学
疾病
生物化学
作者
Longping V. Tse,Yixuan J. Hou,Elizabeth McFadden,Lee Re,Trevor Scobey,Sarah R. Leist,David R. Martinez,Rita M. Meganck,Alexandra Schäfer,Boyd Yount,Teresa Mascenik,John M. Powers,Scott H. Randell,Yi Zhang,Lingshu Wang,John R. Mascola,Jason S. McLellan,Ralph S. Baric
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2023-09-27
卷期号:15 (715)
被引量:5
标识
DOI:10.1126/scitranslmed.adg5567
摘要
The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)-related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV/li/GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/Mpro protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV-neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo-electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.
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