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Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

Sarah M. Roelle, View ORCID ProfileNidhi Shukla, View ORCID ProfileAnh T. Pham, View ORCID ProfileAnna M. Bruchez, View ORCID ProfileKenneth A. Matreyek
doi: https://doi.org/10.1101/2021.12.25.474149
Sarah M. Roelle
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
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Nidhi Shukla
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
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Anh T. Pham
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
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Anna M. Bruchez
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
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Kenneth A. Matreyek
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
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  • ORCID record for Kenneth A. Matreyek
  • For correspondence: kenneth.matreyek@case.com
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Abstract

Viral spillover from animal reservoirs can trigger public health crises and cripple the world economy. Knowing which viruses are primed for zoonotic transmission can focus surveillance efforts and mitigation strategies for future pandemics. Successful engagement of receptor protein orthologs is necessary during cross-species transmission. The clade 1 sarbecoviruses including SARS-CoV and SARS-CoV-2 enter cells via engagement of ACE2, while the receptor for clade 2 and clade 3 remains largely uncharacterized. We developed a mixed cell pseudotyped virus infection assay to determine whether various clade 2 and 3 sarbecovirus spike proteins can enter HEK 293T cells expressing human or Rhinolophus horseshoe bat ACE2 proteins. The receptor binding domains from BtKY72 and Khosta-2 used human ACE2 for entry, while BtKY72 and Khosta-1 exhibited widespread use of diverse rhinolophid ACE2s. A lysine at ACE2 position 31 appeared to be a major determinant of the inability of these RBDs to use a certain ACE2 sequence. The ACE2 protein from R. alcyone engaged all known clade 3 and clade 1 receptor binding domains. We observed little use of Rhinolophus ACE2 orthologs by the clade 2 viruses, supporting the likely use of a separate, unknown receptor. Our results suggest that clade 3 sarbecoviruses from Africa and Europe use Rhinolophus ACE2 for entry, and their spike proteins appear primed to contribute to zoonosis under the right conditions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding: This research was supported by a National Institutes of Health (NIH) grant AI141620 (KAM), AI156907 (KAM), GM142886 (KAM), and AI161275 (AMB). The Cytometry & Imaging Microscopy Shared Resource of the Case Comprehensive Cancer Center was supported by NIH grants P30CA043703 and S10OD021559.

  • Competing interests: None

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 27, 2021.
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Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains
Sarah M. Roelle, Nidhi Shukla, Anh T. Pham, Anna M. Bruchez, Kenneth A. Matreyek
bioRxiv 2021.12.25.474149; doi: https://doi.org/10.1101/2021.12.25.474149
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Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains
Sarah M. Roelle, Nidhi Shukla, Anh T. Pham, Anna M. Bruchez, Kenneth A. Matreyek
bioRxiv 2021.12.25.474149; doi: https://doi.org/10.1101/2021.12.25.474149

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