Breadth of ACE2 receptor usage predicts host range and antigenic relatedness across bat sarbecoviruses
Year: 2026
Type: article
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.
Source: PLoS Biology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,500
Funders: Bill and Melinda Gates Foundation, Wellcome Trust, Coalition for Epidemic Preparedness Innovations, École Polytechnique Fédérale de Lausanne, Université de Genève, Université de Lausanne, Shenzhen University, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Science Fund for Distinguished Young Scholars
Awards: BBSRC National Bioscience Research Infrastructure: Low Containment Services and Science Platforms, BBSRC IAA The Pirbright Institute, G2919144128, The Oxford Interdisciplinary Bioscience Doctoral Training Partnership, The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic, Host Responses to Viral Infection: A fundamental understanding of immune response, G5621985085, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation, G6085025897, G6488532267, Virus Life Cycles at Multiple Scales: Virus-host interactions controlling species-specific outcomes, G7703542511, Beyond polyclonal antibody responses: dissecting susceptibility to newly emerging SARS-CoV-2 variants, G8415457339, The Pirbright Institute - to support the establishment of a veterinary vaccine manufacturing and innovation centre, G2P – Global Knowledge Exchange to Enable In Country Risk Assessment of SARS CoV-2 Variants, G9000847649, UK International coronavirus network (UK-ICN), Virus Life Cycles at Multiple Scales: Biology of virus-infected cells
OpenAlex ID: W7215042982