Post by Nadica (She/Her) on Sept 11, 2024 4:48:27 GMT
Dual-role epitope on SARS-CoV-2 spike enhances and neutralizes viral entry across different variants - Published Sept 5, 2024
Abstract
Grasping the roles of epitopes in viral glycoproteins is essential for unraveling the structure and function of these proteins. Up to now, all identified epitopes have been found to either neutralize, have no effect on, or enhance viral entry into cells. Here, we used nanobodies (single-domain antibodies) as probes to investigate a unique epitope on the SARS-CoV-2 spike protein, located outside the protein’s receptor-binding domain. Nanobody binding to this epitope enhances the cell entry of prototypic SARS-CoV-2, while neutralizing the cell entry of SARS-CoV-2 Omicron variant. Moreover, nanobody binding to this epitope enhances both receptor binding activity and post-attachment activity of prototypic spike, explaining the enhanced viral entry. The opposite occurs with Omicron spike, explaining the neutralized viral entry. This study reveals a unique epitope that can both enhance and neutralize viral entry across distinct viral variants, suggesting that epitopes may vary their roles depending on the viral context. Consequently, antibody therapies should be assessed across different viral variants to confirm their efficacy and safety.
Author summary
Antibodies bind to specific epitopes on viral surface glycoproteins to perform their function: inhibiting viral infection, having no effect, or, in rare cases, enhancing viral infection. In our research, we used nanobodies (small, single-domain antibodies from camelid animals) as probes and identified a unique epitope on the SARS-CoV-2 spike protein with opposing functions across different SARS-CoV-2 variants. It enhances viral infection in pre-Omicron variants but inhibits it in the Omicron variant. We further investigated the molecular mechanism underlying these opposing effects. Although this epitope is not directly involved in receptor binding, nanobody binding to it modulates receptor binding and post-receptor-binding activities. This study marks the first discovery of a dual-function epitope on the SARS-CoV-2 spike protein that both enhances and inhibits viral infection across different viral variants. This discovery challenges the traditional categorization of epitopes, underscores the complex evolution of the SARS-CoV-2 spike protein, and offers new insights into antiviral antibody therapies.
Abstract
Grasping the roles of epitopes in viral glycoproteins is essential for unraveling the structure and function of these proteins. Up to now, all identified epitopes have been found to either neutralize, have no effect on, or enhance viral entry into cells. Here, we used nanobodies (single-domain antibodies) as probes to investigate a unique epitope on the SARS-CoV-2 spike protein, located outside the protein’s receptor-binding domain. Nanobody binding to this epitope enhances the cell entry of prototypic SARS-CoV-2, while neutralizing the cell entry of SARS-CoV-2 Omicron variant. Moreover, nanobody binding to this epitope enhances both receptor binding activity and post-attachment activity of prototypic spike, explaining the enhanced viral entry. The opposite occurs with Omicron spike, explaining the neutralized viral entry. This study reveals a unique epitope that can both enhance and neutralize viral entry across distinct viral variants, suggesting that epitopes may vary their roles depending on the viral context. Consequently, antibody therapies should be assessed across different viral variants to confirm their efficacy and safety.
Author summary
Antibodies bind to specific epitopes on viral surface glycoproteins to perform their function: inhibiting viral infection, having no effect, or, in rare cases, enhancing viral infection. In our research, we used nanobodies (small, single-domain antibodies from camelid animals) as probes and identified a unique epitope on the SARS-CoV-2 spike protein with opposing functions across different SARS-CoV-2 variants. It enhances viral infection in pre-Omicron variants but inhibits it in the Omicron variant. We further investigated the molecular mechanism underlying these opposing effects. Although this epitope is not directly involved in receptor binding, nanobody binding to it modulates receptor binding and post-receptor-binding activities. This study marks the first discovery of a dual-function epitope on the SARS-CoV-2 spike protein that both enhances and inhibits viral infection across different viral variants. This discovery challenges the traditional categorization of epitopes, underscores the complex evolution of the SARS-CoV-2 spike protein, and offers new insights into antiviral antibody therapies.