Enterovirus-A71 exploits peripherin and Rac1 to invade the central nervous system

Enterovirus-A71 (EV-A71) has been associated with severe neurological forms of Hand, Foot and Mouth Disease (HFMD). EV-A71 infects motorneurons at neuromuscular junctions (NMJs) to invade the central nervous system (CNS). Here, we investigate the role of peripherin (PRPH) during EV-A71 infection, a type III intermediate neurofilament involved in neurodegenerative conditions. In mice infected with EV-A71 PRPH co-localizes with viral particles in the muscles at NMJs, and in the spinal cord. In motor neuron-like and neuroblastoma cell lines, surface-expressed PRPH facilitates viral entry, while intracellular PRPH influences viral genome replication through interactions with structural and non-structural viral components. Importantly, PRPH does not play a role during infection with coxsackievirus A16, another causative agent of HFMD rarely associated with neurological complications; suggesting that EV-A71 ability to exploit PRPH represents a unique attribute for successful CNS invasion. Finally, we show that EV-A71 also exploits some of the many PRPH interacting partners. Of these, small GTP binding protein Rac1 represents a potential druggable host target to limit neuroinvasion of EV-A71. -