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.