Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus DOI Creative Commons
Jimin Lee, Samantha K. Zepeda, Young‐Jun Park

et al.

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(12), P. 1961 - 1973.e11

Published: Nov. 20, 2023

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with antigenicity their spike (S) glycoproteins remain uncharacterized. Here, we show that African bat sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and receptor-binding domain (RBD) mutations further expand promiscuity enable human ACE2 utilization. We determine cryo-EM structure RBD bound to alcyone ACE2, explaining highlighting differences SARS-CoV-1 SARS-CoV-2. Characterization using monoclonal antibody reactivity reveals its distinct relative SARS-CoV-2 identifies cross-neutralizing antibodies for pandemic preparedness. vaccination elicits greater titers cross-reacting vaccine-mismatched 1a sarbecoviruses compared due broader antigenic targeting, motivating inclusion antigens in next-generation vaccines enhanced resilience viral evolution.

Language: Английский

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses DOI Open Access
Yanjia Chen, Xiaoyu Zhao, Hao Zhou

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(3), P. 189 - 199

Published: Sept. 27, 2022

Language: Английский

Citations

283
Broadly neutralizing antibodies target the coronavirus fusion peptide DOI Creative Commons
Cherrelle Dacon, Courtney Tucker, Linghang Peng

et al.

Science, Journal Year: 2022, Volume and Issue: 377(6607), P. 728 - 735

Published: July 12, 2022

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach identify six monoclonal antibodies that bind spike proteins from all seven human-infecting coronaviruses. All conserved fusion peptide region adjacent S2' cleavage site. COV44-62 and COV44-79 neutralize alpha- betacoronaviruses, including severe acute respiratory syndrome 2 (SARS-CoV-2) Omicron subvariants BA.2 BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures antigen-binding fragments SARS-CoV-2 peptide, epitope adopts a helical structure includes arginine residue at limited disease caused by in Syrian hamster model. These findings highlight as candidate next-generation vaccine development.

Language: Английский

Citations

194
Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein DOI Creative Commons
Filippo Bianchini, Virginia Crivelli, Morgan E. Abernathy

et al.

Science Immunology, Journal Year: 2023, Volume and Issue: 8(81)

Published: Jan. 26, 2023

Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy vaccines and antiviral monoclonal antibodies. Continued development immunotherapies vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions virus spike glycoprotein are both functionally relevant averse change, we identified human neutralizing antibodies highly conserved epitopes. Antibody fp.006 binds fusion peptide cross-reacts against coronaviruses four genera, including nine coronaviruses, through recognition motif includes S2' site proteolytic cleavage. hr2.016 targets stem helix neutralizes SARS-CoV-2 variants. sd1.040 subdomain 1, synergizes with rbd.042 for neutralization, and, similar hr2.016, protects mice expressing angiotensin-converting enzyme infection when present as bispecific antibody. Thus, discovery reveals donor-derived cross-reactive Orthocoronavirinae,

Language: Английский

Citations

67
Identification of a conserved S2 epitope present on spike proteins from all highly pathogenic coronaviruses DOI Creative Commons

Rui P. Silva,

Yimin Huang, Annalee W. Nguyen

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 21, 2023

To address the ongoing SARS-CoV-2 pandemic and prepare for future coronavirus outbreaks, understanding protective potential of epitopes conserved across variants lineages is essential. We describe a highly conserved, conformational S2 domain epitope present only in prefusion core β-coronaviruses: apex residues 980–1006 flexible hinge. Antibody RAY53 binds native hinge MERS-CoV spikes on surface mammalian cells mediates antibody-dependent cellular phagocytosis cytotoxicity against spike vitro. Hinge mutations that ablate antibody binding compromise pseudovirus infectivity, but changes elsewhere affect opening dynamics, including those found Omicron BA.1, occlude may evade pre-existing serum antibodies targeting core. This work defines third class while providing insights into potency limitations targeting.

Language: Английский

Citations

66
Germline-encoded amino acid–binding motifs drive immunodominant public antibody responses DOI
Ellen Shrock, Richard T. Timms, Tomasz Kula

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6640)

Published: April 6, 2023

Despite the vast diversity of antibody repertoire, infected individuals often mount responses to precisely same epitopes within antigens. The immunological mechanisms underpinning this phenomenon remain unknown. By mapping 376 immunodominant “public epitopes” at high resolution and characterizing several their cognate antibodies, we concluded that germline-encoded sequences in antibodies drive recurrent recognition. Systematic analysis antibody-antigen structures uncovered 18 human 21 partially overlapping mouse amino acid–binding (GRAB) motifs heavy light V gene segments case studies proved critical for public epitope GRAB represent a fundamental component immune system’s architecture promotes recognition pathogens leads species-specific can exert selective pressure on pathogens.

Language: Английский

Citations

58
Repeated vaccination of inactivated SARS-CoV-2 vaccine dampens neutralizing antibodies against Omicron variants in breakthrough infection DOI Open Access
Bo Gao, Liheng He, Yu-Jie Bao

et al.

Cell Research, Journal Year: 2023, Volume and Issue: 33(3), P. 258 - 261

Published: Jan. 25, 2023

Language: Английский

Citations

54
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
Structure and inhibition of SARS-CoV-2 spike refolding in membranes DOI
Michael W. Grunst, Zhuan Qin, Esteban Dodero‐Rojas

et al.

Science, Journal Year: 2024, Volume and Issue: 385(6710), P. 757 - 765

Published: Aug. 15, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas S1 domain contains high sequence variability, is conserved a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates understand inhibition by antibodies stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into intermediates, which were captured at various stages refolding. Pan-betacoronavirus neutralizing targeting stem-helix bound inhibited prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate process SARS-CoV-2 entry reveal how S2-targeting neutralize infectivity arresting

Language: Английский

Citations

19
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

8
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

6