OmniVira

Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses.

Alexandra L Tse1 Cory M Acreman2 Inna Ricardo-Lax3 Jacob Berrigan1 Gorka Lasso1 Toheeb Balogun4 Fiona L Kearns4 Lorenzo Casalino4 Georgia L McClain3 Amartya Mudry Chandran1 Charlotte Lemeunier1 Rommie E Amaro4 Charles M Rice3 Rohit K Jangra1,5 Jason S McLellan2 Kartik Chandran1 Emily Happy Miller1,6
Affiliations 6 institutions
  1. Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
  2. Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.
  3. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America.
  4. Department of Molecular Biology, University of California San Diego, La Jolla, California, United States of America.
  5. Present address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
  6. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
PMID39546542 DOI10.1371/journal.ppat.1012704 Year2024 Journal PLoS pathogens PLoS Pathog Languageeng Publication statusActive
Active Last checked 2026-10-01 03:31:10 Source: NCBI PubMed

Abstract

Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent bat CoVs to investigate their cell entry mechanisms. Unexpectedly, the successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2. A second substitution in the S1 N-terminal domain, uncovered through the rescue and serial passage of a virus bearing the FPPR substitution, further enhanced spike:ACE2 interaction and viral entry. Our findings identify genetic pathways for adaptation by bat CoVs during spillover and host-to-host transmission, fitness trade-offs inherent to these pathways, and potential Achilles' heels that could be targeted with countermeasures.

Supporting text Virus Host Location
Chiroptera 376 Spike Glycoprotein, Coronavirus 276 Virus Internalization 100 Angiotensin-Converting Enzyme 2 178 Animals 1981 Coronavirus Infections 172 HEK293 Cells 61 Humans 1455 Receptors, Virus 208 SARS-CoV-2 456 Severe acute respiratory syndrome-related coronavirus 79

Evidence records

3 total
Functional Mechanism
3 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE8583 Receptor Usage
Key finding

The spike receptor-binding domain of the SARS-like bat coronavirus SHC014-CoV interacts with the cellular receptor ACE2, and a fusion peptide–proximal substitution increases ACE2-mediated viral entry.

Virus
SARS-related coronavirus
Host
bats Chiroptera Experimental system
Location
Not specified
Supporting text

Unexpectedly, the successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2.

Method
recombinant VSV bearing bat coronavirus spike | coronavirus pseudovirus entry assay | receptor-binding domain analysis
Receptors
ACE2
Evidence type Molecular Adaptation
2 records
OVE8581 Molecular Adaptation
Key finding

A novel substitution in the S2 fusion peptide-proximal region of SHC014-CoV spike increased viral entry by enhancing receptor-binding domain accessibility to ACE2.

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

The successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2.

Genes or proteins
spike | S2 fusion peptide-proximal region | receptor-binding domain
Receptors
ACE2
Mutations
novel substitution in the S2 fusion peptide-proximal region
Mechanism types
receptor binding | host entry
OVE8582 Molecular Adaptation
Key finding

A second substitution in the S1 N-terminal domain of bat coronavirus spike further enhanced spike–ACE2 interaction and viral entry efficiency.

Virus
Coronaviridae
Host
Not specified
Location
Not specified
Supporting text

A second substitution in the S1 N-terminal domain, uncovered through the rescue and serial passage of a virus bearing the FPPR substitution, further enhanced spike:ACE2 interaction and viral entry.

Genes or proteins
spike | S1 N-terminal domain
Receptors
ACE2
Mutations
second substitution in the S1 N-terminal domain
Mechanism types
receptor binding | host entry