Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses
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.
Authors
- Inna Ricardo-Lax (ORCID: https://orcid.org/0000-0002-9590-9692)
- Jason S. McLellan (ORCID: https://orcid.org/0000-0003-3991-542X)
- Toheeb A. Balogun (ORCID: https://orcid.org/0000-0002-6267-425X)
- Jacob Berrigan
- Charles M. Rice (ORCID: https://orcid.org/0000-0003-3087-8079)
- Alexandra L. Tse (ORCID: https://orcid.org/0000-0002-1629-6526)
- Gorka Lasso (ORCID: https://orcid.org/0000-0001-5355-323X)
- Emily Happy Miller (ORCID: https://orcid.org/0000-0002-0640-5653)
- Lorenzo Casalino (ORCID: https://orcid.org/0000-0003-3581-1148)
- Rohit K. Jangra (ORCID: https://orcid.org/0000-0002-3119-0869)
- Georgia L. McClain
- Fiona L. Kearns (ORCID: https://orcid.org/0000-0002-5469-9035)
- Rommie Elizabeth Amaro (ORCID: https://orcid.org/0000-0002-9275-9553)
- Kartik Chandran (ORCID: https://orcid.org/0000-0003-0232-7077)
- Cory M. Acreman (ORCID: https://orcid.org/0009-0004-8064-2245)
- Charlotte Lemeunier
- Amartya Mudry Chandran
Institutions
- Albert Einstein College of Medicine (US)
- University of California San Diego (US)
- Louisiana State University Health Sciences Center Shreveport (US)
- Rockefeller University (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1371/journal.ppat.1012704
- Citations
- 9
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 3.50
Funders
- Bill and Melinda Gates Foundation
- Welch Foundation
- G. Harold and Leila Y. Mathers Charitable Foundation
- Meyer Foundation
- Shurl and Kay Curci Foundation
- Thermo Fisher Scientific
- Fast Grants
- Department of Biotechnology, Ministry of Science and Technology, India
- A.G. Leventis Foundation
- National Institutes of Health
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences