Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses
7 affiliations
- 1The Pirbright Institute, Pirbright, Woking, United Kingdom
- 2Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- 3School of Pharmacy, International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University Medical School, Shenzhen, China
- 4Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom
- 5Laboratory of Biological Electron Microscopy (LBEM), Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne, Rte Cantonale, Lausanne, Switzerland
- 6Department of Infectious Disease, Imperial College London, London, United Kingdom
- 7Protein Production and Structure Core Facility (PTPSP), School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Abstract
Sarbecoviruses interact with their receptor, angiotensin-converting enzyme 2 (ACE2), via the receptor-binding domain (RBD) of Spike, the immunodominant target for neutralising antibodies. Understanding the interplay and correlation between ACE2-determined host range and antigenicity is vitally important for understanding the zoonotic potential of related bat sarbecoviruses. Using binding assays, pseudotype-entry assays and a diverse panel of mammalian ACE2 proteins, we examined the host range and related antigenicity of multiple bat coronaviruses. Broad bat ACE2 usage (a generalist phenotype) was most common in clade 1 sarbecoviruses, including SARS-CoV-2 and the BANAL isolates from Laos. In contrast, clade 3 (e.g., RhGB07) and 5 (e.g., Rc-o319) sarbecoviruses exhibited more restricted ACE2 usage (a specialist phenotype). A novel structure for RhGB07 Spike further helped to identify RBD residues associated with this receptor specialism. Interestingly, the generalist phenotypes were largely maintained with more diverse mammalian receptor libraries, including human, non-human primate, livestock, rodent ACE2 and potential intermediate reservoir hosts (e.g., civet, racoon dog, pangolin), while specialists, like RhGB07, exhibited wider phenotypic diversity. The impact of SARS-CoV-2’s continued evolution in humans was also examined, identifying an expanding and/or shifting pattern of generalism for variants, especially Omicron and its sub-lineages. Furthermore, we compared and correlated these entry phenotypes with antigenicity using sera from SARS-CoV-2 convalescent individuals. Clade 1 viruses, phylogenetically related to SARS-CoV-2, were antigenically the most similar, with robust evidence for cross-neutralisation; however, there was still evidence for limited cross-neutralisation across the entire sub-genus. Finally, using monoclonal antibodies, derived from COVID-19 vaccinees with breakthrough infections, we pin-pointed the antibody epitope classes responsible for wider neutralisation. Our research indicates that generalist ACE2-using sarbecoviruses are phylogenetically and antigenically related to SARS-CoV-2.
How ACE2 receptor usage shapes sarbecovirus host range and antigenicity remains unclear. In a sarbecovirus screen against 34 ACE2 receptors, this study identifies viruses with generalist and specialist tropism, which correlates with antigenicity, with robust cross-neutralization of closely-related viruses but some cross-neutralisation across the entire viral sub-genus.
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BibTeX
@article{thakur2026breadth,
title = {{Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses}},
author = {Nazia Thakur and Joseph Newman and Dongchun Ni and Jeffrey Seow and Abigail L. Hay and Yeonjae Lee and Ayush Upadhyay and Babatunde E. Ekundayo and John A. Hammond and Thomas P. Peacock and Kelvin Lau and Katie J. Doores and Dalan Bailey},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3003944},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003944},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses
AU - Nazia Thakur
AU - Joseph Newman
AU - Dongchun Ni
AU - Jeffrey Seow
AU - Abigail L. Hay
AU - Yeonjae Lee
AU - Ayush Upadhyay
AU - Babatunde E. Ekundayo
AU - John A. Hammond
AU - Thomas P. Peacock
AU - Kelvin Lau
AU - Katie J. Doores
AU - Dalan Bailey
PY - 2026
DA - 2026/10/01
JO - PLOS Biology
DO - 10.1371/journal.pbio.3003944
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003944
AB - Sarbecoviruses interact with their receptor, angiotensin-converting enzyme 2 (ACE2), via the receptor-binding domain (RBD) of Spike, the immunodominant target for neutralising antibodies. Understanding the interplay and correlation between ACE2-determined host range and antigenicity is vitally important for understanding the zoonotic potential of related bat sarbecoviruses. Using binding assays, pseudotype-entry assays and a diverse panel of mammalian ACE2 proteins, we examined the host range and related antigenicity of multiple bat coronaviruses. Broad bat ACE2 usage (a generalist phenotype) was most common in clade 1 sarbecoviruses, including SARS-CoV-2 and the BANAL isolates from Laos. In contrast, clade 3 (e.g., RhGB07) and 5 (e.g., Rc-o319) sarbecoviruses exhibited more restricted ACE2 usage (a specialist phenotype). A novel structure for RhGB07 Spike further helped to identify RBD residues associated with this receptor specialism. Interestingly, the generalist phenotypes were largely maintained with more diverse mammalian receptor libraries, including human, non-human primate, livestock, rodent ACE2 and potential intermediate reservoir hosts (e.g., civet, racoon dog, pangolin), while specialists, like RhGB07, exhibited wider phenotypic diversity. The impact of SARS-CoV-2’s continued evolution in humans was also examined, identifying an expanding and/or shifting pattern of generalism for variants, especially Omicron and its sub-lineages. Furthermore, we compared and correlated these entry phenotypes with antigenicity using sera from SARS-CoV-2 convalescent individuals. Clade 1 viruses, phylogenetically related to SARS-CoV-2, were antigenically the most similar, with robust evidence for cross-neutralisation; however, there was still evidence for limited cross-neutralisation across the entire sub-genus. Finally, using monoclonal antibodies, derived from COVID-19 vaccinees with breakthrough infections, we pin-pointed the antibody epitope classes responsible for wider neutralisation. Our research indicates that generalist ACE2-using sarbecoviruses are phylogenetically and antigenically related to SARS-CoV-2. How ACE2 receptor usage shapes sarbecovirus host range and antigenicity remains unclear. In a sarbecovirus screen against 34 ACE2 receptors, this study identifies viruses with generalist and specialist tropism, which correlates with antigenicity, with robust cross-neutralization of closely-related viruses but some cross-neutralisation across the entire viral sub-genus.
SN - 1545-7885
ER -