OmniVira

Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus.

Jimin Lee1 Samantha K Zepeda1 Young-Jun Park2,3 Ashley L Taylor4 Joel Quispe1 Cameron Stewart1 Elizabeth M Leaf2,5 Catherine Treichel2,5 Davide Corti6 Neil P King2,5 Tyler N Starr4 David Veesler2,7
Affiliations 7 institutions
  1. Department of Biochemistry, University of Washington, Seattle, WA, USA.
  2. Department of Biochemistry, University of Washington, Seattle, WA, USA
  3. Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  4. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  5. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  6. Humabs Biomed SA, a Subsidiary of Vir. Biotechnology, 6500 Bellinzona, Switzerland.
  7. Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID37989312 DOI10.1016/j.chom.2023.10.018 Year2023 Journal Cell host & microbe Cell Host Microbe Languageeng Statusppublish

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 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.

Supporting text Virus Host Location
ACE2 54 bat coronaviruses 2 clade 3 sarbecovirus 1 cryo-EM 7 PRD-0038 1 receptor tropism 1 SARS-CoV-2 550 spike glycoprotein 6 vaccine 6 zoonotic spillover 11 Chiroptera 371 Severe acute respiratory syndrome-related coronavirus 78 Angiotensin-Converting Enzyme 2 177 Animals 1948 Antibodies, Viral 212 Humans 1440 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 Tropism 11

Evidence records

3 total
Functional Mechanism
3 records · 2 evidence types
Evidence type Receptor Usage
2 records
OVE7561 Receptor Usage
Key finding

The African Rhinolophus bat clade 3 sarbecovirus PRD-0038 spike protein uses angiotensin-converting enzyme 2 (ACE2) receptors broadly and can utilize human ACE2.

Virus
SARS-related coronavirus Sarbecovirus
Host
Rhinolophus Experimental system human Homo sapiens Experimental system
Location
Not specified
Supporting text

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.

Method
receptor-binding assays | functional receptor usage analysis
Receptors
angiotensin-converting enzyme 2 (ACE2) | human ACE2
Host factors
receptor-binding domain (RBD) mutations
OVE7562 Receptor Usage
Key finding

Cryo-EM structure shows PRD-0038 receptor-binding domain binds Rhinolophus alcyone ACE2, explaining receptor tropism.

Virus
SARS-related coronavirus
Host
Halcyon horseshoe bat Rhinolophus alcyone Experimental system
Location
Not specified
Supporting text

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.

Method
cryo-EM structural analysis | receptor-binding domain complex determination
Receptors
ACE2 | Rhinolophus alcyone ACE2
Evidence type Molecular Adaptation
1 records
OVE7563 Molecular Adaptation
Key finding

RBD mutations in the clade 3 sarbecovirus PRD-0038 broaden receptor tropism and enable utilization of human ACE2, demonstrating adaptive receptor binding and host-range expansion.

Virus
SARS-related coronavirus
Host
Not specified
Location
Not specified
Supporting text

The African Rhinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad ACE2 usage and receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization.

Genes or proteins
spike (S) glycoprotein | receptor-binding domain (RBD)
Receptors
ACE2 | human ACE2 | Rhinolophus alcyone ACE2
Mechanism types
receptor binding | receptor usage | host-range expansion