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- Title
A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
- Authors
Tse, Longping V.; Hou, Yixuan J.; McFadden, Elizabeth; Lee, Rhianna E.; Scobey, Trevor D.; Leist, Sarah R.; Martinez, David R.; Meganck, Rita M.; Schäfer, Alexandra; Yount, Boyd L.; Mascenik, Teresa; Powers, John M.; Randell, Scott H.; Zhang, Yi; Wang, Lingshu; Mascola, John; McLellan, Jason S.; Baric, Ralph S.
- Abstract
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. Editor's summary: Monoclonal antibodies and antivirals are essential tools to treat SARS-CoV-2 infection, and such approaches could be applied to other coronaviruses. Here, Tse et al. investigated whether antibodies that neutralize MERS-CoV and antivirals that inhibit SARS-CoV-2 could be used against a MERS-like bat coronavirus, BtCoV-422. The authors found that a MERS-CoV neutralizing antibody, JC57-11, efficiently neutralized BtCoV-422. BtCoV-422 replication was also potently inhibited by antivirals such as remdesivir. Together, these data suggest that the toolkit developed to treat SARS-CoV-2 could be used for other coronaviruses should they emerge in human populations. —Courtney Malo
- Subjects
MIDDLE East; MIDDLE East respiratory syndrome; CORONAVIRUSES; MERS coronavirus; COVID-19; RECOMBINANT viruses; HIV protease inhibitors
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 715, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adg5567