Loss of FCoV-23 spike domain 0 enhances fusogenicity and entry kinetics
M. Alejandra Tortorici, Annette Choi, C 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
Abstract
. 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.