SARS‐CoV‐2 Alpha, Beta, and Delta variants display enhanced Spike‐mediated syncytia formation. (25th October 2021)

• Record Type: Journal Article
• Authors: Rajah, Maaran Michael; Hubert, Mathieu; Bishop, Elodie; Saunders, Nell; Robinot, Remy; Grzelak, Ludivine; Planas, Delphine; Dufloo, Jérémy; Gellenoncourt, Stacy; Bongers, Alice; Zivaljic, Marija; Planchais, Cyril; Guivel‐Benhassine, Florence; Porrot, Françoise; Mouquet, Hugo; Chakrabarti, Lisa A; Buchrieser, Julian; Schwartz, Olivier
• Is Part Of: EMBO journal. Volume 40:Number 24(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-25
• Subjects: coronavirus -- fusion -- SARS‐CoV‐2 -- spike -- syncytia; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021108944
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Severe COVID‐19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS‐CoV‐2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared with the ancestral D614G strain. Alpha and Beta replicated similarly to D614G strain in Vero, Caco‐2, Calu‐3, and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Variant spike proteins displayed higher ACE2 affinity compared with D614G. Alpha, Beta, and D614G fusion was similarly inhibited by interferon‐induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes modified fusogenicity, binding to ACE2 or recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS‐CoV‐2 emerging variants display enhanced syncytia formation. SYNOPSIS: The spike protein of the novel SARS‐CoV‐2 variants are comparative more fusogenic than the earlier strains. The mutations in the variant spike protein modulate syncytia formation, ACE2 binding, and antibody escape. The spike protein of Alpha, Beta and Delta, in the absence of other viral proteins, induce more syncytia than the ancestral D614G strain. The ACE2 affinity of the variant spike proteins correlates to their fusogenicity. Variant associated mutations P681H, D1118H, and D215G augment cell‐cell fusion, while antibody escape mutation E484K, K417N and Δ242‐244 hamper it. Abstract : Spike protein mutations expressed by emerging SARS‐CoV‐2 variants‐of‐concern differentially affect host cell‐to‐cell fusion, ACE2 receptor binding, and antibody escape.