Cross‐Species Transmission and Structural Adaptive Evolution: Implications of the FCoV‐23 Pandemic for the Evolution of Coronaviruses

Two recent studies identified feline coronavirus 23 (FCoV-23), a recombinant feline coronavirus responsible for severe feline infectious peritonitis outbreaks in Cyprus. Recombination analysis revealed two breakpoints flanking a region spanning ORF1b and the spike gene, sharing 96.5% identity with the hypervirulent canine coronavirus (CCoV) strain NA/09, with phylogenetic analysis confirming that the FCoV-23 spike gene clusters with CCoV-2 while the genomic backbone clusters with FCoV-1. Structurally, conserved receptor binding domain (RBD) residues (Y549/Q551/W592) enable FCoV-23 to recognize aminopeptidase N (APN) across feline, canine, porcine, and avian hosts, while reduced human APN binding results from loss of N739 glycosylation due to a single substitution at position 741. Deletion of the N-terminal domain 0 (D0), present in over 90% of Cyprus cases, enhances cell entry kinetics and promotes macrophage tropism. Comparative analysis with APN-utilizing CoVs, including CCoV-HuPn-2018 and HCoV-229E, highlights the zoonotic potential of this CoV lineage and underscores the need for enhanced surveillance and pandemic preparedness.