Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related to SARS-CoV-2, has been identified in one horseshoe-bat species. Here we characterize the ability of the S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, pangolin coronavirus (PgCoV), RaTG13, and LyRa11, a bat virus similar to SARS-CoV-1, to bind a range of ACE2 orthologs. We observed that the PgCoV RBD bound human ACE2 at least as efficiently as the SARS-CoV-2 RBD, and that both RBDs bound pangolin ACE2 efficiently. We also observed a high level of variability in binding to closely related horseshoe-bat ACE2 orthologs consistent with the heterogeneity of their RBD-binding regions. However five consensus horseshoe-bat ACE2 residues enhanced ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 pseudoviruses by an enzymatically inactive immunoadhesin form of human ACE2 (hACE2-NN-Fc). Two of these mutations impaired neutralization of SARS-CoV-1 pseudoviruses. An hACE2-NN-Fc variant bearing all five mutations neutralized both SARS-CoV-2 pseudovirus and infectious virus more efficiently than wild-type hACE2-NN-Fc. These data suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of soluble ACE2.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
PLoS pathogens - 17(2021), 4 vom: 09. Apr., Seite e1009501 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mou, Huihui [VerfasserIn] |
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| Links: |
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| Themen: |
Angiotensin-Converting Enzyme 2 |
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| Anmerkungen: |
Date Completed 10.05.2021 Date Revised 25.05.2021 published: Electronic-eCollection UpdateOf: bioRxiv. 2020 Jun 30;:. - PMID 32637954 Citation Status MEDLINE |
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| doi: |
10.1371/journal.ppat.1009501 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM32391117X |
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| 100 | 1 | |a Mou, Huihui |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2 |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 10.05.2021 | ||
| 500 | |a Date Revised 25.05.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a UpdateOf: bioRxiv. 2020 Jun 30;:. - PMID 32637954 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related to SARS-CoV-2, has been identified in one horseshoe-bat species. Here we characterize the ability of the S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, pangolin coronavirus (PgCoV), RaTG13, and LyRa11, a bat virus similar to SARS-CoV-1, to bind a range of ACE2 orthologs. We observed that the PgCoV RBD bound human ACE2 at least as efficiently as the SARS-CoV-2 RBD, and that both RBDs bound pangolin ACE2 efficiently. We also observed a high level of variability in binding to closely related horseshoe-bat ACE2 orthologs consistent with the heterogeneity of their RBD-binding regions. However five consensus horseshoe-bat ACE2 residues enhanced ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 pseudoviruses by an enzymatically inactive immunoadhesin form of human ACE2 (hACE2-NN-Fc). Two of these mutations impaired neutralization of SARS-CoV-1 pseudoviruses. An hACE2-NN-Fc variant bearing all five mutations neutralized both SARS-CoV-2 pseudovirus and infectious virus more efficiently than wild-type hACE2-NN-Fc. These data suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of soluble ACE2 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Receptors, Virus |2 NLM | |
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| 700 | 1 | |a Quinlan, Brian D |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Haiyong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Guanqun |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Shoujiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lizhou |e verfasserin |4 aut | |
| 700 | 1 | |a Davis-Gardner, Meredith E |e verfasserin |4 aut | |
| 700 | 1 | |a Gardner, Matthew R |e verfasserin |4 aut | |
| 700 | 1 | |a Crynen, Gogce |e verfasserin |4 aut | |
| 700 | 1 | |a DeVaux, Lindsey B |e verfasserin |4 aut | |
| 700 | 1 | |a Voo, Zhi Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, Charles C |e verfasserin |4 aut | |
| 700 | 1 | |a Alpert, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Rader, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Gack, Michaela U |e verfasserin |4 aut | |
| 700 | 1 | |a Choe, Hyeryun |e verfasserin |4 aut | |
| 700 | 1 | |a Farzan, Michael |e verfasserin |4 aut | |
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