Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody

JCI Insight, Journal Year: 2024, Volume and Issue: 9(10)

Published: May 21, 2024

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk severe Thus, development broadly protective and an understanding underlying mechanisms are great importance. Here, we isolated from donors with breakthrough infection Omicron subvariants using a single-B cell screening platform. We identified mAb, O5C2, which possesses broad-spectrum neutralization antibody-dependent cell-mediated cytotoxic activities variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted unusually large epitope within receptor-binding domain spike protein overlapped angiotensin-converting enzyme 2 binding interface. Furthermore, effectively protected BA.5 in vivo mediating changes transcriptomes enriched genes involved apoptosis interferon responses. Our findings provide insights into pan-protective SARS-CoV-2.

Language: Английский

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Engineering customized viral receptors for various coronaviruses

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 25, 2024

Abstract Coronaviruses display versatile receptor usage, yet in-depth characterization of coronaviruses lacking known identities has been impeded by the absence feasible infection models 1,2 . Here, we developed an innovative strategy to engineer functional customized viral receptors (CVRs). The modular design relies on building frameworks comprising various function modules and generating specific epitope-targeting binding domains. We showed key factors for CVRs efficiently facilitate spike cleavage, membrane fusion, pseudovirus entry, authentic virus propagation coronaviruses, resembling their native receptors. Applying this strategy, delineated accessible epitopes SARS-CoV-2 CVR elucidated mechanism entry supported amino-terminus domain (NTD) targeting S2L20-CVR. Furthermore, created CVR-expressing cells assessing antibodies inhibitors against 12 representative from six subgenera, most which Notably, a pan-sarbecovirus sarbecoviruses, as well replicable HKU3 strain RsHuB2019A 3 Through combining HKU5-specific with reverse genetics, successfully rescued cultured wild-type fluorescence protein-incorporated HKU5, receptor-unidentified merbecovirus. Our study demonstrated great potential in establishing receptor-independent models, paving way studying viruses that are challenging culture due lack susceptible cells.

Language: Английский

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SARS-CoV-2 neutralization and protection of hamsters via nasal administration of a humanized neutralizing antibody

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

Published: July 8, 2024

ABSTRACT Monoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since start pandemic, eight monoclonal against SARS-CoV-2 were granted emergency use authorization. High mutation rate virus has led to emergence highly transmissible variants efficiently evading vaccine-induced immunity. This highlights importance identifying broadly neutralizing with therapeutic potential. In this study, we a panel murine (mAb) identify subset that bound and neutralized broad spectrum variants. Intranasal delivery XR10, most promising mAb, protected hamsters infection by Alpha Delta We next humanized XR10 mAb using combination CDR-grafting Vernier zones preservation approaches (CRVZ) create antibody ranked based on their spike binding ability neutralization. Of these, XR10v48 demonstrated best neutralize was protective in when given as single 50 µg/kg intranasal dose at time viral challenge. features 34 key amino acid residues retained from progenitor. Our work introduces potent demonstrates activity vivo low dose.

Language: Английский

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Determinants of species-specific utilization of ACE2 by human and animal coronaviruses

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

Published: March 31, 2023

ABSTRACT Utilization of human ACE2 allowed several bat coronaviruses (CoVs), including the causative agent COVID-19, to infect humans either directly or via intermediate hosts. Here, we analyzed ability Spike proteins from 24 animal CoVs use receptors across nine reservoir, potential and We show that overall SARS-CoV-2 Omicron variants evolved more efficient usage but mutation R493Q in BA.5 disrupts utilization Greater horseshoe bats. Spikes most showed species-specific differences usage, partly due variations residues 31, 41 354. Mutation T403R RaTG13 CoV all orthologs analysed for viral entry. Sera COVID-19 vaccinated individuals neutralized a range Sarbecoviruses. Our results define determinants receptor diverse suggest vaccination may protect against future zoonoses SARS-CoV-related viruses. Highlights bats Variations 354 affect by coronavirus Residue R403 protein allow broad effective neutralize Sarbecoviruses

Language: Английский

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Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

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

Published: Nov. 23, 2023

The emergence of SARS-CoV-2 lineages derived from Omicron, including BA.2.86 (nicknamed “Pirola”) and its relative, JN.1, has raised concerns about their potential impact on public personal health due to numerous novel mutations. Despite this, predicting implications based solely mutation counts proves challenging. Empirical evidence JN.1’s increased immune evasion capacity in relation previous variants is mixed. To improve predictions beyond what possible counts, we conducted extensive silico analyses the binding affinity between RBD different (Wuhan-Hu-1, BA.1/B.1.1.529, BA.2, XBB.1.5, BA.2.86, JN.1) neutralizing antibodies vaccinated or infected individuals, as well human angiotensin-converting enzyme 2 (ACE2) receptor. We observed no statistically significant difference JN.1 other variants. Therefore, conclude that new have pronounced escape infection compared However, minor reductions for both ACE2 were noted JN.1. discuss findings highlight need modeling docking studies go above basic serological neutralization analysis. Future research this area will benefit structural memory B-cell should emphasize importance choosing appropriate samples assess protection provided by vaccination infection. More-over, fitness benefits genomic variation outside be investigated. This contributes understanding variants’ health. Taken together, work introduces a paradigm functional epidemiology ongoing efforts combat evolving pandemic prepare hazards.

Language: Английский

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