Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans DOI Creative Commons
Amin Addetia, Cameron Stewart,

Albert J. Seo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 2, 2024

Abstract Middle-East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections endemic regions. Most vaccines therapeutics development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts, however, are limited by a poor understanding of antibody responses elicited infection along with their durability, fine specificity contribution distinct S antigenic sites neutralization. To address this knowledge gap, we analyzed S-directed binding neutralizing titers plasma collected from individuals infected 2017-2019 (prior COVID-19 pandemic). We observed that antibodies peak 1 6 weeks after symptom onset/hospitalization, persist for at least months, broadly neutralize camel strains. show subunit is immunodominant targeting , particularly RBD, account most activity. Antigenic site mapping revealed polyclonal frequently RBD epitopes, exposed irrespective trimer conformation, whereas 2 epitopes rare, similar SARS-CoV-2. Our data reveal unprecedented details humoral immune infection, which will guide vaccine therapeutic design.

Language: Английский

The Evolution and Biology of SARS-CoV-2 Variants DOI Open Access
Amalio Telenti, Emma B. Hodcroft, David L. Robertson

et al.

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2022, Volume and Issue: 12(5), P. a041390 - a041390

Published: April 20, 2022

Our understanding of the still unfolding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic would have been extremely limited without study genetics and evolution this new human coronavirus. Large-scale genome-sequencing efforts provided close to real-time tracking global spread diversification SARS-CoV-2 since its entry into population in late 2019. These data underpinned analysis origins, epidemiology, adaptations population: principally immune evasion increasing transmissibility. SARS-CoV-2, despite being a pathogen, was highly capable human-to-human transmission. During rapid humans, has evolved independent forms, so-called "variants concern," that are better optimized for The most important adaptation bat progenitor both SARS-CoV-1 infection (and other mammals) is use angiotensin-converting enzyme (ACE2) receptor. Relaxed structural constraints provide plasticity SARS-related spike protein permitting it accommodate significant amino acid replacements antigenic consequence compromising ability bind ACE2. Although bulk research justifiably concentrated on viral as main determinant changes transmissibility, there accumulating evidence contribution regions proteome virus-host interaction. Whereas levels community transmission recombinants genetically distinct variants at present low, when divergent cocirculate, recombination between clades detected, risk viruses with properties emerge. Applying computational machine learning methods genome sequence sets generate experimentally verifiable predictions will serve an early warning system novel variant surveillance be future vaccine planning. Omicron, latest concern, focused attention step change events, "shift," opposed incremental "drift" antigenicity. Both increase transmissibility shift Omicron led readily causing infections fully vaccinated and/or previously infected. Omicron's virulence, while reduced relative concern replaced, Delta, very much premised past exposure individuals clear signal boosted vaccination protects from disease. Currently, proven itself dangerous pathogen unpredictable evolutionary capacity, leading too great not ensure all world screened by sequencing, protected through available affordable vaccines, non-punitive strategies place detecting responding concern.

Language: Английский

Citations

158
ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies DOI Creative Commons
Jun Siong Low, Josipa Jerak, M. Alejandra Tortorici

et al.

Science, Journal Year: 2022, Volume and Issue: 377(6607), P. 735 - 742

Published: July 12, 2022

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind all human-infecting proteins from severe acute respiratory syndrome 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide acquire affinity breadth through somatic mutations. Despite targeting conserved motif, only some show neutralizing activity in vitro against alpha- betacoronaviruses, including animal coronaviruses WIV-1 PDF-2180. Two selected also neutralize Omicron BA.1 BA.2 authentic viruses reduce burden pathology vivo. Structural functional analyses showed peptide–specific bound with different modalities cryptic epitope hidden prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme (ACE2) or ACE2-mimicking mAbs.

Language: Английский

Citations

146
Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines DOI Creative Commons

Liyan Guo,

Sheng Lin, Zimin Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 10, 2023

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), has devastating impacts on the public health and economy. Rapid viral antigenic evolution led to continual generation new variants. Of special note is recently expanding Omicron subvariants that are capable immune evasion from most existing neutralizing antibodies (nAbs). This posed challenges for prevention treatment COVID-19. Therefore, exploring broad-spectrum antiviral agents combat emerging variants imperative. In sharp contrast massive accumulation mutations within SARS-CoV-2 receptor-binding domain (RBD), S2 fusion subunit remained highly conserved among Hence, S2-based therapeutics may provide effective cross-protection against Here, we summarize developed inhibitors (e.g., nAbs, peptides, proteins, small-molecule compounds) candidate vaccines targeting elements in subunit. main focus includes all targetable elements, namely, peptide, stem helix, heptad repeats 1 (HR1-HR2) bundle. Moreover, a detailed summary characteristics action-mechanisms each class cross-reactive inhibitors, which should guide promote future design coronaviruses.

Language: Английский

Citations

48
Human coronavirus HKU1 recognition of the TMPRSS2 host receptor DOI Creative Commons
Matthew McCallum, Young‐Jun Park, Cameron Stewart

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(16), P. 4231 - 4245.e13

Published: July 3, 2024

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. molecular basis of binding TMPRSS2 determinants receptor tropism remain elusive. We designed an active construct enabling high-yield recombinant production in cells this key therapeutic target. determined a cryo-electron microscopy structure the RBD bound TMPRSS2, providing blueprint interactions supporting viral entry explaining specificity for among orthologous proteases. identified orthologs from five mammalian orders promoting S-mediated into along with residues governing usage. Our data show that motif is site vulnerability neutralizing antibodies suggest uses S conformational masking glycan shielding balance immune evasion engagement.

Language: Английский

Citations

16
Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor DOI
Jing Chen, Wei Zhang, Yang Li

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

6
Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses DOI Creative Commons

Chengbao Ma,

Chen Liu, Young‐Jun Park

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related (MERSr-CoVs) infecting Pipistrellus nathusii (P.nat)-MOW15-22 and PnNL2018B-use ACE2 as their receptor, narrow ortholog specificity. Cryoelectron microscopy structures the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected entirely binding mode, mapping >45 Å away from any other known ACE2-using coronaviruses. Functional profiling orthologs 105 mammalian species led to identification host tropism determinants, including N432-glycosylation restricting viral recognition, design a soluble P.nat mutant potent neutralizing activity. Our findings reveal usage for merbecoviruses found in European bats, underscoring extraordinary diversity recognition modes among promiscuity this receptor.

Language: Английский

Citations

5
Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses DOI
Young‐Jun Park, Chen Liu, Jimin Lee

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

5
Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein DOI Creative Commons
M. Alejandra Tortorici, Alexandra C. Walls,

Anshu Joshi

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(13), P. 2279 - 2291.e17

Published: May 27, 2022

Language: Английский

Citations

63
The coronavirus recombination pathway DOI Creative Commons
Heather Wells, Cassandra M. Bonavita,

Isamara Navarrete-Macias

et al.

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(6), P. 874 - 889

Published: June 1, 2023

Recombination is thought to be a mechanism that facilitates cross-species transmission in coronaviruses, thus acting as driver of coronavirus spillover and emergence. Despite its significance, the recombination poorly understood, limiting our potential estimate risk novel recombinant coronaviruses emerging future. As tool for understanding recombination, here, we outline framework pathway coronaviruses. We review existing literature on including comparisons naturally observed genomes well vitro experiments, place findings into framework. highlight gaps illustrated by how further experimental research critical disentangling molecular from external environmental pressures. Finally, describe an increased can inform pandemic predictive intelligence, with retrospective emphasis SARS-CoV-2.

Language: Английский

Citations

24
A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus DOI
Longping V. Tse, Yixuan J. Hou, Elizabeth McFadden

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(715)

Published: Sept. 27, 2023

The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets countermeasure design. Middle East respiratory syndrome (MERS)–related coronaviruses (CoVs) remain a pressing concern global health preparedness. Using metagenomic sequence data CoV reverse genetics, we recovered full-length wild-type MERS-like BtCoV/ li /GD/2014-422 (BtCoV-422) recombinant virus, as well two reporter viruses, evaluated their potential susceptibility to currently available countermeasures. Similar MERS-CoV, BtCoV-422 efficiently used other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins entry receptors an alternative DPP4-independent infection route in presence exogenous proteases. also replicated primary airway, lung endothelial, fibroblast cells, although less than MERS-CoV. However, shows minor signs 288/330 DPP4 transgenic mice. Several antivirals, including nucleoside analogs 3C-like/M pro protease inhibitors, demonstrated potent inhibition against vitro. Serum from mice that received MERS-CoV mRNA vaccine showed reduced neutralizing activity BtCoV-422. Although most MERS-CoV–neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized potently. A cryo–electron microscopy structure JC57-11 complex with spike revealed mechanism cross-neutralization involving occlusion site, highlighting its broadly mAb group 2c CoVs use receptor. These studies provide critical insights into candidates development.

Language: Английский

Citations

24