Tweet
PLoS Pathog
. 2021 Apr 9;17(4):e1009501.
doi: 10.1371/journal.ppat.1009501. Online ahead of print.
Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2
Huihui Mou 1 , Brian D Quinlan 1 , Haiyong Peng 1 , Guanqun Liu 2 , Yan Guo 1 , Shoujiao Peng 1 , Lizhou Zhang 1 , Meredith E Davis-Gardner 1 , Matthew R Gardner 1 , Gogce Crynen 3 , Lindsey B DeVaux 1 , Zhi Xiang Voo 1 , Charles C Bailey 4 , Michael D Alpert 4 , Christoph Rader 1 , Michaela U Gack 2 , Hyeryun Choe 1 , Michael Farzan 1
Affiliations
- PMID: 33836016
- DOI: 10.1371/journal.ppat.1009501
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.