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
- David Veesler
2025-07-10
The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat 1,2 . 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.