Journal Article

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

Davis-Gardner, Meredith E., Guo, Yan, Choe, Hyeryun, Mou, Huihui, Bailey, Charles C., Voo, Zhi Xiang, Liu, Guanqun, Quinlan, Brian D., Peng, Haiyong, Peng, Shoujiao, Zhang, Lizhou, Crynen, Gogce, DeVaux, Lindsey B., Alpert, Michael D., Farzan, Michael, Gardner, Matthew R., Rader, Christoph, Gack, Michaela U.

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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