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

[Emily]

https://www.biorxiv.org/content/10.1101/2020.06.29.178459v1.abstract

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

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

bioRxiv 2020.06.29.178459; doi: https://doi.org/10.1101/2020.06.29.178459 This article is a preprint and has not been certified by peer review
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DISCUSSION


Here we show that three ACE2 orthologs – human, pangolin, and R. macrotis bat – associate with the SARS2-RBD more efficiently than with the SARS1-RBD. In contrast, pig, dog, palm civet, and mouse orthologs bound more efficiently to SARS1-RBD, and neither RBD bound R. pusillus bat or rat ACE2. Unexpectedly the RBD of the SARS-like coronavirus RaTG13 isolated from horseshoe bats (R. affinis) did not bind either horseshoe bat ACE2 ortholog tested, indicating that the not-yet-described R. affinis ACE2 varies in significant ways from these horseshoe-bat orthologs. However, unlike the SARS2-RBD, the RaTG13-RBD bound both rat and mouse ACE2 orthologs efficiently...

 

[Emily]

Full summary.

SUMMARY

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 SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat (R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

 

[sharon sanders]

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