tetano
Editor, Senior Moderator
Sci Transl Med
. 2023 Sep 27;15(715):eadg5567.
doi: 10.1126/scitranslmed.adg5567. Epub 2023 Sep 27. A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus
Longping V Tse[SUP] 1 [/SUP], Yixuan J Hou[SUP] 2 [/SUP], Elizabeth McFadden[SUP] 3 [/SUP], Rhianna E Lee[SUP] 4 [/SUP], Trevor D Scobey[SUP] 2 [/SUP], Sarah R Leist[SUP] 2 [/SUP], David R Martinez[SUP] 2 [/SUP], Rita M Meganck[SUP] 1 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Boyd L Yount[SUP] 2 [/SUP], Teresa Mascenik[SUP] 4 [/SUP], John M Powers[SUP] 2 [/SUP], Scott H Randell[SUP] 4 [/SUP], Yi Zhang[SUP] 5 [/SUP], Lingshu Wang[SUP] 5 [/SUP], John Mascola[SUP] 5 [/SUP], Jason S McLellan[SUP] 3 [/SUP], Ralph S Baric[SUP] 2 [/SUP]
Affiliations
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/M[SUP]pro[/SUP] 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.
. 2023 Sep 27;15(715):eadg5567.
doi: 10.1126/scitranslmed.adg5567. Epub 2023 Sep 27. A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus
Longping V Tse[SUP] 1 [/SUP], Yixuan J Hou[SUP] 2 [/SUP], Elizabeth McFadden[SUP] 3 [/SUP], Rhianna E Lee[SUP] 4 [/SUP], Trevor D Scobey[SUP] 2 [/SUP], Sarah R Leist[SUP] 2 [/SUP], David R Martinez[SUP] 2 [/SUP], Rita M Meganck[SUP] 1 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Boyd L Yount[SUP] 2 [/SUP], Teresa Mascenik[SUP] 4 [/SUP], John M Powers[SUP] 2 [/SUP], Scott H Randell[SUP] 4 [/SUP], Yi Zhang[SUP] 5 [/SUP], Lingshu Wang[SUP] 5 [/SUP], John Mascola[SUP] 5 [/SUP], Jason S McLellan[SUP] 3 [/SUP], Ralph S Baric[SUP] 2 [/SUP]
Affiliations
- PMID: 37756379
- DOI: 10.1126/scitranslmed.adg5567
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/M[SUP]pro[/SUP] 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.