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Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2.
PLoS Pathog. 2021 04; 17(4):e1009501.PP

Abstract

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.

Authors+Show Affiliations

Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Bioinformatics and Statistics Core, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Emmune, Inc., Juno Beach, FL, United States of America.Emmune, Inc., Juno Beach, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

33836016

Citation

Mou, Huihui, et al. "Mutations Derived From Horseshoe Bat ACE2 Orthologs Enhance ACE2-Fc Neutralization of SARS-CoV-2." PLoS Pathogens, vol. 17, no. 4, 2021, pp. e1009501.
Mou H, Quinlan BD, Peng H, et al. Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2. PLoS Pathog. 2021;17(4):e1009501.
Mou, H., Quinlan, B. D., Peng, H., Liu, G., Guo, Y., Peng, S., Zhang, L., Davis-Gardner, M. E., Gardner, M. R., Crynen, G., DeVaux, L. B., Voo, Z. X., Bailey, C. C., Alpert, M. D., Rader, C., Gack, M. U., Choe, H., & Farzan, M. (2021). Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2. PLoS Pathogens, 17(4), e1009501. https://doi.org/10.1371/journal.ppat.1009501
Mou H, et al. Mutations Derived From Horseshoe Bat ACE2 Orthologs Enhance ACE2-Fc Neutralization of SARS-CoV-2. PLoS Pathog. 2021;17(4):e1009501. PubMed PMID: 33836016.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2. AU - Mou,Huihui, AU - Quinlan,Brian D, AU - Peng,Haiyong, AU - Liu,Guanqun, AU - Guo,Yan, AU - Peng,Shoujiao, AU - Zhang,Lizhou, AU - Davis-Gardner,Meredith E, AU - Gardner,Matthew R, AU - Crynen,Gogce, AU - DeVaux,Lindsey B, AU - Voo,Zhi Xiang, AU - Bailey,Charles C, AU - Alpert,Michael D, AU - Rader,Christoph, AU - Gack,Michaela U, AU - Choe,Hyeryun, AU - Farzan,Michael, Y1 - 2021/04/09/ PY - 2020/12/05/received PY - 2021/03/24/accepted PY - 2021/04/21/revised PY - 2021/4/10/pubmed PY - 2021/5/11/medline PY - 2021/4/9/entrez SP - e1009501 EP - e1009501 JF - PLoS pathogens JO - PLoS Pathog VL - 17 IS - 4 N2 - 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. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/33836016/Mutations_derived_from_horseshoe_bat_ACE2_orthologs_enhance_ACE2_Fc_neutralization_of_SARS_CoV_2_ DB - PRIME DP - Unbound Medicine ER -