BREAKING! French Study Alarmingly Reveals That Emerging SARS-CoV-2 Variants Possess Enhanced Syncytia Formation!
Source: SARS-CoV-2 Emerging Variants Oct 06, 2021 3 years, 1 month, 1 week, 20 hours, 8 minutes ago
SARS-CoV-2 Emerging Variants: A new study by French researchers from the Institut Pasteur-Paris, Université de Paris, Vaccine Research Institute-France and Sorbonne Université-Paris has alarmingly found that the various new emerging SARS-CoV-2 variants display enhanced syncytia formation! These findings confirm that the emerging variants are getting more dangerous for humans!
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Syncytia is formed by fusion of an infected cells with neighboring cells leading to the formation of multi-nucleate enlarged cells. This event is induced by surface expression of viral fusion protein that are fusogenic directly at the host cell membrane. Syncytia canonly happen with viruses able to directly fuse at the cellular surface without the need of endocytosis.
Typically, 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, the study team first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared to 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 to 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.
The study team further found that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation.
The study findings were published in the peer reviewed EMBO Journal.
https://www.embopress.org/doi/abs/10.15252/embj.2021108944
The SARS-CoV-2 coronavirus was first detected during an outbreak in late 2019 in Wuhan, China. Since the emergence of this virus, the original strain has been supplanted by several variants, which have arisen from a variety of mutations.
Importantly it has been observed that the Spike (S) protein of the virus is the location at which several of these mutations have occurred, which has given many variants the ability to evade the neutralizing antibody response.
Basically, the subunits S1 and S2 make up the SARS-CoV-2 S protein. The S1 subunit comprises the receptor-binding domain (RBD) and the N-terminal domain (NTD). The RBD interacts with the angiotensin-converting enzyme 2 (ACE2) receptor and is the primary target for neutralizing antibodies. The functions of the NTD are not yet fully understood, but it is hypothesized that it may be associated with receptor recognition, glycan-binding, and pre-fusion-to-post-fusion conformational changes.
The study team compared the replication and syncytia forming potential of Alpha, Beta, and D614G strains in human cell lines and primary airway cells.
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SARS-CoV-2-Emerging-Variants study team also characterized the fusogenicity of the Alpha and Beta variants' S proteins and the contributions of each mutation in syncytia formation, ACE2 binding, and evasion of neutralizing antibodies.
Lastly, the study team analyzed the syncytia forming potential and ACE2 binding capacity of the Delta variant S protein.
The study team utilized an S-Fuse assay using U2OS-ACE2 GFP-split cells to induce syncytia in potential SARS-CoV-2 variants.
The study findings revealed that the Alpha and Beta variants formed more numerous and larger infected syncytia upon infection of S-Fuse cells compared to both the original Wuhan strain and the D146G strain. By calculating the total syncytia area and then normalizing the nuclei number, the authors quantitatively characterized the differences in fusogenicity.
The study findings showed that significantly more syncytia were produced by the Alpha and Beta variants, relative to D614G, approximately 4.5 and 3-fold respectively, after 20 hours of infection with the same multiplicity of infection (MOI). Vero cells carrying the GFP-split system were generated to characterize syncytia formation in a cell line expressing endogenous ACE2.
Interestingly following 48 hours of infection with the same MOI, Alpha and Beta variants were still found to have produced significantly more syncytia when compared to D614G, which suggests that the Alpha and Beta variants are more fusogenic.
It was also found that the Alpha, Beta, and D614G variants are all affected differently by certain neutralizing antibodies.
The D614G variant for example, is restricted by the neutralizing monoclonal antibody 48 (mAb48), but the Alpha and Beta variants are not.
The study teams determined which mutations in S protein variants contributed to the reduced recognition by neutralizing antibodies by utilizing flow cytometry to observe the binding of a panel of four monoclonal antibodies (mAbs) to different mutants of S proteins.
For example, the MAb48 did not recognize the Alpha and Beta variants, and it also did not bind to the K417N mutant.
Both the Alpha and Beta variants were also not recognized by mAb71 and did not bind to their NTD ΔY144 and Δ242-244 mutations. A decrease in S-mediated fusion is caused by the mutations Δ242-244 and K417N, which suggests a trade-off between antibody escape and fusion.
Importantly the Beta variant was not recognized by mAb98, although the lack of binding was not a consequence of the associated mutations. This suggests antibody escape may be affected by a combined effect on the structure of the S protein.
Hence despite a reduction in protein fusion ability, several mutations found in the S proteins of variants are advantageous in escaping antibodies.
The study team characterized the replication, antibody recognition, fusogenicity, and ACE2 binding of the Alpha and Beta variants of SARS-CoV-2 and the role of S-associated mutations. The study team detailed insights into the S-mediated fusogenicity of the variants but did not examine the conformational changes that individual mutations or a combination of mutations may elicit.
The study team show when compared to the D614G variant, the S proteins of the Alpha, Beta, and Delta variants bind to ACE2 more efficiently and are more fusogenic.
The study findings also showed that the Delta spike also triggers faster fusion relative to D614G. This infers that as time goes by, the emerging SARS-CoV-2 variants are evolving and displaying even more enhanced syncytia formation.
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