SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions to endemic infection patterns are associated with changes in the spike (S) proteins that direct virus-cell entry. These changes generate antigenic drift and thereby allow virus main...
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Public Library of Science (PLoS)
2024-12-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012757&type=printable |
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| author | Enya Qing Julisa Salgado Alexandria Wilcox Tom Gallagher |
| author_facet | Enya Qing Julisa Salgado Alexandria Wilcox Tom Gallagher |
| author_sort | Enya Qing |
| collection | DOAJ |
| description | Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions to endemic infection patterns are associated with changes in the spike (S) proteins that direct virus-cell entry. These changes generate antigenic drift and thereby allow virus maintenance in the face of prevalent human antiviral antibodies. These changes also fine tune virus-cell entry dynamics in ways that optimize transmission and infection into human cells. Focusing on the latter aspect, we evaluated the effects of several S protein substitutions on virus-cell membrane fusion, an essential final step in enveloped virus-cell entry. Membrane fusion is executed by integral-membrane "S2" domains, yet we found that substitutions in peripheral "S1" domains altered late-stage fusion dynamics, consistent with S1-S2 heterodimers cooperating throughout cell entry. A specific H655Y change in S1 stabilized a fusion-intermediate S protein conformation and thereby delayed membrane fusion. The H655Y change also sensitized viruses to neutralization by S2-targeting fusion-inhibitory peptides and stem-helix antibodies. The antibodies did not interfere with early fusion-activating steps; rather they targeted the latest stages of S2-directed membrane fusion in a novel neutralization mechanism. These findings demonstrate that single amino acid substitutions in the S proteins both reset viral entry-fusion kinetics and increase sensitivity to antibody neutralization. The results exemplify how selective forces driving SARS-CoV-2 fitness and antibody evasion operate together to shape SARS-CoV-2 evolution. |
| format | Article |
| id | doaj-art-fb8b725c177c4bbbb8023aa315d6dfba |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-fb8b725c177c4bbbb8023aa315d6dfba2025-08-20T02:49:01ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-12-012012e101275710.1371/journal.ppat.1012757SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization.Enya QingJulisa SalgadoAlexandria WilcoxTom GallagherSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions to endemic infection patterns are associated with changes in the spike (S) proteins that direct virus-cell entry. These changes generate antigenic drift and thereby allow virus maintenance in the face of prevalent human antiviral antibodies. These changes also fine tune virus-cell entry dynamics in ways that optimize transmission and infection into human cells. Focusing on the latter aspect, we evaluated the effects of several S protein substitutions on virus-cell membrane fusion, an essential final step in enveloped virus-cell entry. Membrane fusion is executed by integral-membrane "S2" domains, yet we found that substitutions in peripheral "S1" domains altered late-stage fusion dynamics, consistent with S1-S2 heterodimers cooperating throughout cell entry. A specific H655Y change in S1 stabilized a fusion-intermediate S protein conformation and thereby delayed membrane fusion. The H655Y change also sensitized viruses to neutralization by S2-targeting fusion-inhibitory peptides and stem-helix antibodies. The antibodies did not interfere with early fusion-activating steps; rather they targeted the latest stages of S2-directed membrane fusion in a novel neutralization mechanism. These findings demonstrate that single amino acid substitutions in the S proteins both reset viral entry-fusion kinetics and increase sensitivity to antibody neutralization. The results exemplify how selective forces driving SARS-CoV-2 fitness and antibody evasion operate together to shape SARS-CoV-2 evolution.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012757&type=printable |
| spellingShingle | Enya Qing Julisa Salgado Alexandria Wilcox Tom Gallagher SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. PLoS Pathogens |
| title | SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. |
| title_full | SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. |
| title_fullStr | SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. |
| title_full_unstemmed | SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. |
| title_short | SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization. |
| title_sort | sars cov 2 omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012757&type=printable |
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