Loss of FCoV-23 spike domain 0 enhances fusogenicity and entry kinetics

M. Alejandra Tortorici, Annette Choi, Cecily A. Gibson, Jimin Lee, Jack T. Brown, Cameron Stewart, Anshu Joshi, Sheri Harari, Isabelle Willoughby, Catherine Treichel, Elizabeth M. Leaf, Jesse D. Bloom, Neil P. King, Christine Tait-Burkard, Gary R. Whittaker and David Veesler ()
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M. Alejandra Tortorici: University of Washington
Annette Choi: Cornell University
Cecily A. Gibson: University of Washington
Jimin Lee: University of Washington
Jack T. Brown: University of Washington
Cameron Stewart: University of Washington
Anshu Joshi: University of Washington
Sheri Harari: Fred Hutchinson Cancer Center
Isabelle Willoughby: University of Washington
Catherine Treichel: University of Washington
Elizabeth M. Leaf: University of Washington
Jesse D. Bloom: Howard Hughes Medical Institute
Neil P. King: University of Washington
Christine Tait-Burkard: University of Edinburgh
Gary R. Whittaker: Cornell University
David Veesler: University of Washington

Nature, 2025, vol. 645, issue 8079, 235-243

Abstract: Abstract The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat1,2. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis. Here we report cryogenic electron microscopy structures of two FCoV-23 spike isoforms that correspond to the in-host loss of domain 0 observed in clinical samples. The loss of domain 0 markedly enhances the fusogenicity and kinetics of entry into cells and possibly enables biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N orthologues as receptors and reveal the molecular determinants of receptor species tropism, including a glycan that modulates human receptor engagement. We define antigenic relationships among alphacoronaviruses that infect humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody that inhibits FCoV-23 entry. Our results pave the way for the development of vaccines and therapeutics that target this highly pathogenic virus.

Date: 2025
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DOI: 10.1038/s41586-025-09155-z

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