Introduction: The ongoing emergence of SARS-CoV-2 variants poses significant challenges to existing therapeutics. The spike (S) glycoprotein is central to both viral entry and cell-to-cell transmission via syncytia formation, a process that confers resistance to neutralizing antibodies. The mechanisms underlying this resistance, particularly in relation to spike-mediated fusion, remain poorly understood. Methods: We analyzed two clinical SARS-CoV-2 isolates differing by a single amino acid substitution in the S protein. Using biochemical and cell-based assays, we evaluated entry kinetics, syncytia formation, and the neutralizing efficacy of convalescent sera. These parameters were further correlated with S-mediated cell-cell fusion activity. Results: The single amino acid substitution significantly altered entry kinetics and enhanced syncytia formation. This modification did not diminished the neutralizing capacity of convalescent sera, but it increased the efficiency of S-induced cell-cell fusion. These findings highlight the mutation’s impact on viral transmissibility and immune evasion. Discussion: Our study demonstrates that even minor changes in the S protein can profoundly influence SARS-CoV-2 transmissibility and resistance to antibody-mediated neutralization. Understanding the molecular basis of S-mediated cell-cell fusion is crucial for anticipating the impact of emerging variants and developing next-generation therapeutic strategies. These insights provide a framework for predicting variant fitness and optimizing treatment approaches against future SARS-CoV-2 variants.

Single spike mutation differentiating XBB.1 and XBB.1.5 enhances SARS-CoV-2 cell-to-cell transmission and facilitates serum-mediated enhancement / Criscuolo, Elena; Giuliani, Benedetta; Castelli, Matteo; Cavallaro, Mattia; Sisti, Sofia; Burioni, Roberto; Ferrari, Davide; Mancini, Nicasio; Locatelli, Massimo; Clementi, Nicola. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - 15:(2024). [10.3389/fimmu.2024.1501200]

Single spike mutation differentiating XBB.1 and XBB.1.5 enhances SARS-CoV-2 cell-to-cell transmission and facilitates serum-mediated enhancement

Criscuolo, Elena
Co-primo
Project Administration
;
Giuliani, Benedetta
Co-primo
Methodology
;
Castelli, Matteo
Software
;
Cavallaro, Mattia
Software
;
Sisti, Sofia
Methodology
;
Burioni, Roberto
Writing – Review & Editing
;
Mancini, Nicasio
Writing – Review & Editing
;
Clementi, Nicola
Ultimo
Funding Acquisition
2024-01-01

Abstract

Introduction: The ongoing emergence of SARS-CoV-2 variants poses significant challenges to existing therapeutics. The spike (S) glycoprotein is central to both viral entry and cell-to-cell transmission via syncytia formation, a process that confers resistance to neutralizing antibodies. The mechanisms underlying this resistance, particularly in relation to spike-mediated fusion, remain poorly understood. Methods: We analyzed two clinical SARS-CoV-2 isolates differing by a single amino acid substitution in the S protein. Using biochemical and cell-based assays, we evaluated entry kinetics, syncytia formation, and the neutralizing efficacy of convalescent sera. These parameters were further correlated with S-mediated cell-cell fusion activity. Results: The single amino acid substitution significantly altered entry kinetics and enhanced syncytia formation. This modification did not diminished the neutralizing capacity of convalescent sera, but it increased the efficiency of S-induced cell-cell fusion. These findings highlight the mutation’s impact on viral transmissibility and immune evasion. Discussion: Our study demonstrates that even minor changes in the S protein can profoundly influence SARS-CoV-2 transmissibility and resistance to antibody-mediated neutralization. Understanding the molecular basis of S-mediated cell-cell fusion is crucial for anticipating the impact of emerging variants and developing next-generation therapeutic strategies. These insights provide a framework for predicting variant fitness and optimizing treatment approaches against future SARS-CoV-2 variants.
2024
SARS-CoV-2, Spike, COVID-19, XBB.1, XBB.1.5, neutralizing antibodies, fusion
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/173356
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