Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2

• Published in: PLoS pathogens Vol. 17; no. 4; p. e1009501
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.04.2021; Public Library of Science (PLoS)
• Subjects: ACE2; Angiotensin converting enzyme; Angiotensin-converting enzyme 2; Binding; Biology and life sciences; Coronaviruses; Disease transmission; Gene mutations; Genetic aspects; Health aspects; Infections; Medicine and health sciences; Middle East respiratory syndrome; Mutation; Neutralization; Protein binding; Proteins; Research and Analysis Methods; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Stomatitis; Viral diseases; Virulence (Microbiology); Viruses; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009501

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.