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

• 成果类型: Article
• 署名作者: Tortorici, M. Alejandra; Choi, Annette; Gibson, Cecily A.; Lee, Jimin; Brown, Jack T.; Stewart, Cameron; Joshi, Anshu; Harari, Sheri; Willoughby, Isabelle; Treichel, Catherine; Leaf, Elizabeth M.; Bloom, Jesse D.; King, Neil P.; Tait-Burkard, Christine; Whittaker, Gary R.; Veesler, David
• 署名单位: University of Washington; University of Washington Seattle; Cornell University; Howard Hughes Medical Institute; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; University of Edinburgh; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Roslin Institute; Cornell University; Cornell University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1507
• DOI: 10.1038/s41586-025-09155-z
• 发表日期: 2025-09-04
• 关键词: respiratory syndrome coronavirus; aminopeptidase-n; molecular characterization; cell entry; receptor; glycoprotein; Visualization; determinants; validation; attachment

摘要

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.