Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

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Abstract

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 Rinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad ACE2 usage and that RBD mutations further expand receptor promiscuity and enable human ACE2 utilization. We determined a cryoEM structure of the PRD-0038 RBD bound to R. alcyone ACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryoEM and monoclonal antibody reactivity revealed its distinct antigenicity relative to SARS-CoV-2 and identified PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicited greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared to 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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A Novel Coronavirus from Patients with Pneumonia in China, 2019

Na Zhu, Dingyu Zhang, Wenling Wang … (2020)

Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Author and article information

Journal

Journal ID (nlm-ta): bioRxiv

Journal ID (publisher-id): BIORXIV

Title: bioRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 13 September 2023

Electronic Location Identifier: 2023.09.12.557371

Affiliations

[1 ]Department of Biochemistry, University of Washington, Seattle, Washington, USA

[2 ]Howard Hughes Medical Institute, Seattle, WA 98195, USA

[3 ]Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA

[4 ]Institute for Protein Design, University of Washington, Seattle, WA 98195, USA

[5 ]Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.

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[&]

These authors contributed equally

Author Contributions

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.

[* ]Correspondence: dveesler@ 123456uw.edu

Article

DOI: 10.1101/2023.09.12.557371

PMC ID: 10515872

PubMed ID: 37745523

SO-VID: ff67f7da-d18f-419e-9dd4-8e984d3337db

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Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

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Novel Coronavirus Disease COVID-19

Most cited references 103

A Novel Coronavirus from Patients with Pneumonia in China, 2019

A pneumonia outbreak associated with a new coronavirus of probable bat origin

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

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