Evolutionary and structural basis of SLAM utilization in morbilliviruses - Its implications for host range and cross-species transmission

Morbilliviruses, including measles virus (MV), canine distemper virus (CDV), and cetacean morbillivirus, pose a significant threat to humans and animals. While the host range of morbilliviruses is generally well-defined, severe cross-species transmission events also have been reported. Their entry into immune cells, the primary targets of morbilliviruses, relies on the signaling lymphocytic activation molecule (SLAM), a receptor whose species-specific variations influence viral host range. However, the extent to which SLAM diversity is a barrier to cross-species transmission remains poorly understood. In this study, we systematically investigated SLAM-mediated host specificity. We found that most morbilliviruses efficiently utilize SLAM from multiple host species, except for human SLAM. Among the morbilliviruses tested, only MV efficiently utilized human SLAM. Bats are natural reservoirs for many zoonotic viruses. Recent discoveries of novel morbilliviruses in bats provide new insights into morbillivirus evolution. Bats may have played a significant role in morbillivirus evolution because bat (Myotis) SLAM also functioned as an efficient receptor for multiple morbilliviruses. Unlike other morbilliviruses, MV utilized Myotis bat SLAM inefficiently. We conducted an MV adaptation experiment with Myotis bat SLAM to better understand SLAM recognition by morbilliviruses. MV readily adapted to utilize Myotis bat SLAM by acquiring a single N187Y mutation in its hemagglutinin protein, and computational structural modeling and fragment molecular orbital calculations with molecular dynamics simulations revealed key interaction changes that facilitated MVs adaptation to Myotis bat SLAM. These findings highlight the adaptability of morbilliviruses in utilizing diverse animal SLAMs. Notably, hypothetical ancestral SLAMs reconstructed in this study acted as universal receptors for all morbilliviruses. These results reinforced that morbillivirus receptor usage is primarily supported by evolutionarily conserved structural features of SLAM, highlighting a molecular basis that enables morbilliviruses to rapidly adapt to diverse animal SLAMs. Author SummaryOur study explores how viruses in the genus morbillivirus, such as measles virus, canine distemper virus, and rinderpest virus, which are notorious for deadly outbreaks in humans and animals, can jump between species. The host range of morbilliviruses is significantly influenced by a receptor molecule on cell surfaces known as the signaling lymphocytic activating molecule (SLAM). By examining SLAMs from various animals, including humans, dolphins, dogs, seals, and bats, we observed how these viruses can infect or adapt to infect different hosts. We found that in some cases slight differences in SLAM may act as initial barriers to cross-species transmission. However, these viruses rapidly overcome such barriers, showing a remarkable ability to adapt. Our research highlights the importance of monitoring these viruses to predict and prevent potential cross-species infections, which is crucial for protecting public health and animal welfare over time.