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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways
The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respira...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061995/ https://www.ncbi.nlm.nih.gov/pubmed/33886690 http://dx.doi.org/10.1371/journal.ppat.1009500 |
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author | Laporte, Manon Raeymaekers, Valerie Van Berwaer, Ria Vandeput, Julie Marchand-Casas, Isabel Thibaut, Hendrik-Jan Van Looveren, Dominique Martens, Katleen Hoffmann, Markus Maes, Piet Pöhlmann, Stefan Naesens, Lieve Stevaert, Annelies |
author_facet | Laporte, Manon Raeymaekers, Valerie Van Berwaer, Ria Vandeput, Julie Marchand-Casas, Isabel Thibaut, Hendrik-Jan Van Looveren, Dominique Martens, Katleen Hoffmann, Markus Maes, Piet Pöhlmann, Stefan Naesens, Lieve Stevaert, Annelies |
author_sort | Laporte, Manon |
collection | PubMed |
description | The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology. |
format | Online Article Text |
id | pubmed-8061995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-80619952021-05-04 The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways Laporte, Manon Raeymaekers, Valerie Van Berwaer, Ria Vandeput, Julie Marchand-Casas, Isabel Thibaut, Hendrik-Jan Van Looveren, Dominique Martens, Katleen Hoffmann, Markus Maes, Piet Pöhlmann, Stefan Naesens, Lieve Stevaert, Annelies PLoS Pathog Research Article The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology. Public Library of Science 2021-04-22 /pmc/articles/PMC8061995/ /pubmed/33886690 http://dx.doi.org/10.1371/journal.ppat.1009500 Text en © 2021 Laporte et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Laporte, Manon Raeymaekers, Valerie Van Berwaer, Ria Vandeput, Julie Marchand-Casas, Isabel Thibaut, Hendrik-Jan Van Looveren, Dominique Martens, Katleen Hoffmann, Markus Maes, Piet Pöhlmann, Stefan Naesens, Lieve Stevaert, Annelies The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title | The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title_full | The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title_fullStr | The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title_full_unstemmed | The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title_short | The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
title_sort | sars-cov-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061995/ https://www.ncbi.nlm.nih.gov/pubmed/33886690 http://dx.doi.org/10.1371/journal.ppat.1009500 |
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