Broad permissiveness of mammalian nectin-4 orthologs for morbilliviruses: a notable exception in dolphin nectin-4

Morbilliviruses utilize signalling lymphocytic activation molecule (SLAM) and nectin-4 as their major cellular receptors and exhibit distinct host specificities despite sharing common receptor usage. While species-specific differences in SLAM have been extensively investigated, the contribution of nectin-4 to morbillivirus host range remains poorly understood because nectin-4 is highly conserved among mammals. Here, we systematically compared the receptor activities of nectin-4 orthologs from human, dolphin, bat, dog and seal for representative morbilliviruses, including measles virus (MV), cetacean morbillivirus (CeMV), canine distemper virus (CDV), phocine distemper virus (PDV) and Myotis bat morbillivirus (MBaMV). Cell-cell fusion, virus infection and plaque assays demonstrated that most nectin-4 orthologs efficiently supported infection by all tested viruses. In contrast, dolphin nectin-4 exhibited markedly reduced receptor activity for MV, PDV and MBaMV, while remaining fully functional for CeMV and CDV. This phenotype was consistently observed with multiple clinical MV isolates. Mutational analyses identified amino acid residue 63 as a key determinant of this receptor specificity. Substitution of glutamic acid at position 63 in dolphin nectin-4 with glycine restored MV receptor activity to a level comparable to that of human nectin-4. These findings demonstrate that nectin-4 is generally a broadly permissive morbillivirus receptor but that specific amino acid differences can substantially influence receptor usage. Our results indicate that receptor compatibility contributes to morbillivirus host range and cross-species transmission while being insufficient on its own to fully explain viral host specificity.