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Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2.
Mou, Huihui; Quinlan, Brian D; Peng, Haiyong; Liu, Guanqun; Guo, Yan; Peng, Shoujiao; Zhang, Lizhou; Davis-Gardner, Meredith E; Gardner, Matthew R; Crynen, Gogce; DeVaux, Lindsey B; Voo, Zhi Xiang; Bailey, Charles C; Alpert, Michael D; Rader, Christoph; Gack, Michaela U; Choe, Hyeryun; Farzan, Michael.
  • Mou H; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Quinlan BD; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Peng H; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Liu G; Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, United States of America.
  • Guo Y; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Peng S; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Zhang L; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Davis-Gardner ME; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Gardner MR; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Crynen G; Bioinformatics and Statistics Core, The Scripps Research Institute, Jupiter, FL, United States of America.
  • DeVaux LB; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Voo ZX; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Bailey CC; Emmune, Inc., Juno Beach, FL, United States of America.
  • Alpert MD; Emmune, Inc., Juno Beach, FL, United States of America.
  • Rader C; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Gack MU; Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, United States of America.
  • Choe H; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
  • Farzan M; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States of America.
PLoS Pathog ; 17(4): e1009501, 2021 04.
Article in English | MEDLINE | ID: covidwho-1175434
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Chiroptera / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009501

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Chiroptera / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009501