A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Science translational medicine - 15(2023), 715 vom: 27. Sept., Seite eadg5567 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tse, Longping V [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 31.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.adg5567 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM362526923 |
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| 520 | |a 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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| 700 | 1 | |a Lee, Rhianna E |e verfasserin |4 aut | |
| 700 | 1 | |a Scobey, Trevor D |e verfasserin |4 aut | |
| 700 | 1 | |a Leist, Sarah R |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Meganck, Rita M |e verfasserin |4 aut | |
| 700 | 1 | |a Schäfer, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Yount, Boyd L |e verfasserin |4 aut | |
| 700 | 1 | |a Mascenik, Teresa |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhang, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lingshu |e verfasserin |4 aut | |
| 700 | 1 | |a Mascola, John |e verfasserin |4 aut | |
| 700 | 1 | |a McLellan, Jason S |e verfasserin |4 aut | |
| 700 | 1 | |a Baric, Ralph S |e verfasserin |4 aut | |
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