Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.
Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 bin...
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Online Access: | https://doi.org/10.1371/journal.ppat.1009772 |
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doaj-05faa96f045b49b8a02895de552988ed2021-08-16T04:30:19ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-08-01178e100977210.1371/journal.ppat.1009772Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.Marta AlenquerFilipe FerreiraDiana LousaMariana ValérioMónica Medina-LopesMarie-Louise BergmanJuliana GonçalvesJocelyne DemengeotRicardo B LeiteJingtao LilueZemin NingCarlos Penha-GonçalvesHelena SoaresCláudio M SoaresMaria João AmorimUnderstanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.https://doi.org/10.1371/journal.ppat.1009772 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marta Alenquer Filipe Ferreira Diana Lousa Mariana Valério Mónica Medina-Lopes Marie-Louise Bergman Juliana Gonçalves Jocelyne Demengeot Ricardo B Leite Jingtao Lilue Zemin Ning Carlos Penha-Gonçalves Helena Soares Cláudio M Soares Maria João Amorim |
spellingShingle |
Marta Alenquer Filipe Ferreira Diana Lousa Mariana Valério Mónica Medina-Lopes Marie-Louise Bergman Juliana Gonçalves Jocelyne Demengeot Ricardo B Leite Jingtao Lilue Zemin Ning Carlos Penha-Gonçalves Helena Soares Cláudio M Soares Maria João Amorim Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. PLoS Pathogens |
author_facet |
Marta Alenquer Filipe Ferreira Diana Lousa Mariana Valério Mónica Medina-Lopes Marie-Louise Bergman Juliana Gonçalves Jocelyne Demengeot Ricardo B Leite Jingtao Lilue Zemin Ning Carlos Penha-Gonçalves Helena Soares Cláudio M Soares Maria João Amorim |
author_sort |
Marta Alenquer |
title |
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. |
title_short |
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. |
title_full |
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. |
title_fullStr |
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. |
title_full_unstemmed |
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. |
title_sort |
signatures in sars-cov-2 spike protein conferring escape to neutralizing antibodies. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2021-08-01 |
description |
Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics. |
url |
https://doi.org/10.1371/journal.ppat.1009772 |
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