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TitleA MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
Journal, issue, pagesSci Transl Med, Vol. 15, Issue 715, Page eadg5567, Year 2023
Publish dateSep 27, 2023
AuthorsLongping V Tse / Yixuan J Hou / Elizabeth McFadden / Rhianna E Lee / Trevor D Scobey / Sarah R Leist / David R Martinez / Rita M Meganck / Alexandra Schäfer / Boyd L Yount / Teresa Mascenik / John M Powers / Scott H Randell / Yi Zhang / Lingshu Wang / John Mascola / Jason S McLellan / Ralph S Baric /
PubMed AbstractThe 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 ...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//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/M 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.
External linksSci Transl Med / PubMed:37756379
MethodsEM (single particle)
Resolution3.0 - 3.2 Å
Structure data

40272

8sak

EMDB-40272, PDB-8sak:
BtCoV-422 in complex with neutralizing antibody JC57-11
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-40306: BtCoV-422 spike in complex with JC57-11 Fab, global map
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-40310: BtCoV-422 spike in complex with JC57-11 Fab, local map
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • middle east respiratory syndrome-related coronavirus
  • macaca (macaques)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / coronavirus / MERS / neutralizing / antibody / MERS-like / merbecovirus / bat / virus / CDRH3 / RBD / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex

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