Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rhinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad angiotensin...

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Published inCell host & microbe Vol. 31; no. 12; pp. 1961 - 1973.e11
Main Authors Lee, Jimin, Zepeda, Samantha K., Park, Young-Jun, Taylor, Ashley L., Quispe, Joel, Stewart, Cameron, Leaf, Elizabeth M., Treichel, Catherine, Corti, Davide, King, Neil P., Starr, Tyler N., Veesler, David
Format Journal Article
LanguageEnglish
Published United States 13.12.2023
Subjects
Angiotensin-Converting Enzyme 2
Animals
Antibodies, Viral
Chiroptera
Humans
SARS-CoV-2 - genetics
Severe acute respiratory syndrome-related coronavirus
Spike Glycoprotein, Coronavirus
Tropism
ACE2
SARS-CoV-2
bat coronaviruses
vaccine
spike glycoprotein
clade 3 sarbecovirus
PRD-0038
receptor tropism
zoonotic spillover
cryo-EM
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Summary:Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rhinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. We determine a cryo-EM structure of the PRD-0038 RBD bound to Rhinolophus alcyone ACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryo-EM and monoclonal antibody reactivity reveals its distinct antigenicity relative to SARS-CoV-2 and identifies PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared with SARS-CoV-2 S due to broader antigenic targeting, motivating the inclusion of clade 3 antigens in next-generation vaccines for enhanced resilience to viral evolution.
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Author Contributions
These authors contributed equally
J.L, S.K.Z., T.S., and D.V. designed the experiments; J.L, S.K.Z. and C.S. recombinantly expressed and purified glycoproteins. J.L and S.K.Z. performed binding assays. J.L carried out pseudovirus entry assays. J.L., S.K.Z, J.Q. and Y.J.P. carried out cryoEM specimen preparation, data collection and processing of PRD-0038 S. J.L., S.K.Z, and Y.J.P. carried out cryoEM specimen preparation, data collection and processing of the PRD-0038 RBD bound to ACE2. J.L., Y.J.P. and D.V built and refined atomic models. E.M.L. and C.T. performed mouse immunizations and blood draws. A.L.T. and T.N.S. carried out DMS experiments. D.C. contributed unique reagents. J.L. and D.V. analyzed the data and wrote the manuscript with input from all authors; N.P.K.,T.N.S. and D.V. supervised the project.
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ISSN:1931-3128
1934-6069
1934-6069
DOI:10.1016/j.chom.2023.10.018