Syncytia Formation Promotes Virus Resistance to Interferon and Neutralizing Antibodies DOI Creative Commons
Tiansheng Li,

Insung Kang,

Zhe Hu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 13, 2023

SUMMARY SARS-CoV-2, like many viruses, generates syncytia. Using SARS-CoV-2 and S (S) expressing recombinant vesicular stomatitis influenza A we show that S-mediated syncytia formation provides resistance to interferons in cultured cells, human small airway-derived air-liquid interface cultures hACE2 transgenic mice. Amino acid substitutions modulate fusogenicity Delta- Omicron-derived have parallel effects on viral interferon resistance. Syncytia also decreases antibody virus neutralization activity cells. These findings explain the continued selection of fusogenic variants during evolution humans and, more generally, viruses despite adverse replication absence innate or adaptive immune pressure.

Language: Английский

Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections DOI Creative Commons
Iris Medits, David Niklas Springer, Marianne Graninger

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 19, 2022

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct to date. As heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after BA.1 or BA.2 sub-lineage infections in live virus tests with BA.1, BA.2, wildtype (WT, B1.1), Delta (B.1.617.2) strains. Serum samples obtained WT three-dose mRNA vaccinations without prior infection were included as controls.Primary yielded reduced neutralizing antibody levels against WT, Delta, while from BA.2-infected showed almost no cross-neutralization other variants. variants was detectable vaccinations, but titers. Vaccination-breakthrough either however, generated equal cross-neutralizing all tested.Our study demonstrates that although are able enhance pre-immune individuals, primary induced mostly variant-specific antibodies, emphasizing differently shaped humoral immunity by two These data thus contribute substantially understanding responses multiple exposures different particular importance for developing vaccination strategies light future emerging

Language: Английский

Citations

40
Evolution of the SARS-CoV-2 Omicron spike DOI Creative Commons
Ruth Parsons, Priyamvada Acharya

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113444 - 113444

Published: Nov. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Language: Английский

Citations

35
SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition DOI
Qianyi E. Zhang, Jared Lindenberger, Ruth Parsons

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(14), P. 2747 - 2764.e7

Published: July 1, 2024

Language: Английский

Citations

9
Effectiveness and durability of BNT162b2 vaccine against hospital and emergency department admissions due to SARS-CoV-2 omicron sub-lineages BA.1 and BA.2 in a large health system in the USA: a test-negative, case-control study DOI
Sara Y. Tartof, Jeff Slezak, Laura Puzniak

et al.

The Lancet Respiratory Medicine, Journal Year: 2022, Volume and Issue: 11(2), P. 176 - 187

Published: Oct. 7, 2022

Language: Английский

Citations

29
Structural analysis of receptor engagement and antigenic drift within the BA.2 spike protein DOI Creative Commons
James W. Saville, Dhiraj Mannar, Xing Zhu

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111964 - 111964

Published: Jan. 1, 2023

The BA.2 sub-lineage of the Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant rapidly supplanted original BA.1 in early 2022. Both lineages threatened efficacy vaccine-elicited antibodies and acquired increased binding to several mammalian ACE2 receptors. Cryoelectron microscopy (cryo-EM) analysis spike (S) glycoprotein complex with mouse (mACE2) identifies BA.1- BA.2-mutated residues Q493R, N501Y, Y505H as complementing non-conserved between human ACE2, rationalizing enhanced S protein-mACE2 interaction for variants. Cryo-EM structures S-human extensively mutated amino-terminal domain (NTD) reveal a dramatic reorganization highly antigenic N1 loop into β-strand, providing an explanation decreased protein isolated from BA.1-convalescent patients. Our reveals structural mechanisms underlying drift evolving landscape.

Language: Английский

Citations

15
RBD-depleted SARS-CoV-2 spike generates protective immunity in cynomolgus macaques DOI Creative Commons
Hélène Letscher,

Delphine Guilligay,

Grégory Effantin

et al.

npj Vaccines, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 30, 2025

Abstract The SARS-CoV-2 pandemic revealed the rapid evolution of circulating strains. This led to new variants carrying mostly mutations within receptor binding domain, which is immunodominant upon immunization and infection. In order steer immune response away from RBD epitopes more conserved domains, we generated S glycoprotein trimers without stabilized them by formaldehyde cross-linking. cryoEM structure demonstrated that SΔRBD folds into native prefusion conformation, one specific cross-link between S2 protomers. was coated onto lipid vesicles, produce synthetic virus-like particles, SΔRBD-LV, were utilized in a heterologous prime-boost strategy. Immunization cynomolgus macaques either three times with mRNA Comirnaty vaccine or two followed SΔRBD-LV showed boost induced similar antibody titers neutralization different variants, including omicron. Upon challenge omicron XBB.3, both only Comirnaty/SΔRBD-LV vaccination schemes conferred overall protection infection for schemes. However, indicated better against lung than strategy alone. Together our findings indicate highly immunogenic provides improved compared third indicative superior antibody-based protection.

Language: Английский

Citations

0
SARS-CoV-2 spike protein: structure, viral entry and variants DOI
Bing Chen, Michael Farzan, Hyeryun Choe

et al.

Nature Reviews Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Language: Английский

Citations

0
Nanoparticle-Supported, Rapid, Digital Quantification of Neutralizing Antibodies Against SARS-CoV-2 Variants DOI
Seyedsina Mirjalili, Md Ashif Ikbal, Ching‐Wen Hou

et al.

Biosensors and Bioelectronics, Journal Year: 2025, Volume and Issue: unknown, P. 117549 - 117549

Published: May 1, 2025

Language: Английский

Citations

0
Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites DOI Creative Commons
Gennady M. Verkhivker, Mohammed Alshahrani,

Grace Gupta

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2009 - 2009

Published: Sept. 27, 2023

A significant body of experimental structures SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable binding pockets. Understanding interplay conformational dynamics changes induced by Omicron identification cryptic dynamic pockets in S is paramount importance as exploring broad-spectrum antiviral agents to combat emerging imperative. In current study, we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, an allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This study provided structural characterization predicted captured sites, revealing critical role modulating cross-talk between sites. We found that mutational variant can induce remodeling stabilization pocket N-terminal domain, while this drastically altered may no longer be available ligand variant. Our results site receptor-binding domain remains stable ranks most favorable but could become fragmented less probable conformations. also uncovered several formed at inter-domain inter-protomer interface, including regions S2 subunit stem helix region, which are consistent with residues transitions antibody recognition. The particularly understanding features proteins, well effects Omicron-variant-specific modulation preferential exploration present new previously underappreciated opportunity therapeutic interventions through conformation-selective targeting involved changes.

Language: Английский

Citations

8
Comparative Analysis of Conformational Dynamics and Systematic Characterization of Cryptic Pockets in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 Spike Complexes with the ACE2 Host Receptor: Confluence of Binding and Structural Plasticity in Mediating Networks of Conserved Allosteric Sites DOI Creative Commons
Mohammed Alshahrani,

Grace Gupta,

Sian Xiao

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2073 - 2073

Published: Oct. 10, 2023

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning cryptic pocket detection in a comparative examination of conformational landscapes systematic characterization allosteric sites SARS-CoV-2 Omicron BA.2, BA.2.75 XBB.1 spike full-length trimer complexes host receptor ACE2. Microsecond simulations, Markov state models mutational energies BA.2 domain revealed increased thermodynamic stabilization variant significant dynamic differences between these variants. Molecular ACE2 complemented studies enabled an in-depth analysis effects on functional adaptability Despite considerable structural similarities, variants can induce unique signatures specific distributions states. Using ensembles ACE2, conducted comprehensive screening to examine role mutations distribution mechanisms emerging sites. This captured all experimentally known discovered networks inter-connected functionally relevant that are governed by variant-sensitive structures. The results detailed how modulate conserved druggable pockets harboring important regions. for understanding roles be used allostery-mediated therapeutic intervention targeting states

Language: Английский

Citations

8