{ "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.\n\nHow 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.", "abstract_shown": true, "affiliations": [ "The Pirbright Institute, Pirbright, Woking, United Kingdom", "Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom", "School of Pharmacy, International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University Medical School, Shenzhen, China", "Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom", "Laboratory of Biological Electron Microscopy (LBEM), Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne, Rte Cantonale, Lausanne, Switzerland", "Department of Infectious Disease, Imperial College London, London, United Kingdom", "Protein Production and Structure Core Facility (PTPSP), School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland" ], "article_type": "Research Article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0 ], "name": "Nazia Thakur" }, { "affs": [ 1 ], "name": "Joseph Newman" }, { "affs": [ 2 ], "name": "Dongchun Ni" }, { "affs": [ 3 ], "name": "Jeffrey Seow" }, { "affs": [ 4 ], "name": "Abigail L. Hay" }, { "affs": [ 5 ], "name": "Yeonjae Lee" }, { "affs": [ 6 ], "name": "Ayush Upadhyay" }, { "name": "Babatunde E. Ekundayo" }, { "name": "John A. Hammond" }, { "name": "Thomas P. Peacock" }, { "name": "Kelvin Lau" }, { "name": "Katie J. Doores" }, { "name": "Dalan Bailey" } ], "bibtex": "https://research.draconitic.com/paper/4w3y5a4mwbj6p.bib", "cited_by": 1, "doi": "10.1371/journal.pbio.3003944", "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003944", "id": "4w3y5a4mwbj6p", "issns": [ "1545-7885" ], "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003944", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2725|SARS-CoV-2 and COVID-19 Research" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antibodies/Monoclonal antibodies" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antibodies/Monoclonal antibodies" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral tropism" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Vertebrates/Amniotes/Mammals/Bats" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Coronaviruses/SARS coronavirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Coronaviruses/SARS coronavirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antibodies" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antibodies/Monoclonal antibodies" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Vertebrates/Amniotes/Mammals/Bats" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antibodies/Monoclonal antibodies" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Research and analysis methods/Immunologic techniques/Immunoassays/Enzyme-linked immunoassays" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Transfection" ] ], "openalex": "W7215042982", "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3003944&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/4w3y5a4mwbj6p.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.pbio.3003944", "source": "plos", "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003944" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" }, { "field": "medicine", "origin": "plos:physiology", "subfield": "physiology" } ], "title": "Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses", "title_text": "Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:37Z", "url": "https://research.draconitic.com/paper/4w3y5a4mwbj6p", "venue": "PLOS Biology", "versions": [] }