Evolutionary and structural basis of SLAMF1 utilization in morbilliviruses—Implications for host range and cross-species transmission

Morbilliviruses, including measles virus (MV), canine distemper virus (CDV), pose a significant threat to humans and animal health due to their capacity to transmit across species. Their entry into primary target cells relies on the signaling lymphocytic activation molecule (SLAM), which exhibits host-specific variability. This study hypothesizes that morbilliviruses utilize heterologous SLAM receptors due to evolutionary conserved structural determinants within SLAM and that slight genetic changes in the viral receptor-binding hemagglutinin (H) protein can facilitate adaptation to new hosts. The research determined that most morbilliviruses utilized multi-species SLAM, but rarely human SLAM (MV excepted). MV adapted to bat SLAM via a single N187Y mutation in H, enhancing fusion by strengthening SLAM-H binding. CDV’s macaque SLAM inefficiency linked to a Y539D mutation while human SLAM’s Arg28 critically restricted CDV entry. Notably, reconstructed ancestral SLAMs broadly permitted entry for all morbilliviruses, emphasizing conserved SLAM properties. This study confirms SLAM’s receptor function is governed by conserved structural features, supporting morbilliviruses’ cross-species transmission potential. The ease of receptor switching, combined with declining MV immunity, underscores the critical need for vigilance and surveillance to prevent future zoonotic events, despite ethical restrictions on human adaptation experiments.
(MKO)