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

Abstract

Enterovirus-A71 (EV-A71) has been associated with severe neurological forms of hand, foot, and mouth disease (HFMD). EV-A71 infects motor neurons 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.

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“…In total, two of the 17 gene products directly compose the cell structure: Tnxb encodes extracellular matrix glycoprotein tenascin X, 52 and Prph encodes intermediate filament peripherin 53 . Tnxb is involved in EMT transition, 54 and Prph is involved in neurite growth and enterovirus‐A71 infection 55 . The other candidates are also associated with virus infection and/or replication.…”

Role of the Intermediate Filament Protein Peripherin in Health and Disease

“…A recent study demonstrates that peripherin colocalizes with virions and acts as a pro-viral factor: surface-expressed peripherin promotes virus entrance in motor neuron-like and neuroblastoma cell lines, while intracellular peripherin is involved in viral genome replication that interacts with capsid and non-structural viral components. EV-A71 also interacts with a number of peripherin interactors such as the small GTP-binding protein Rac1, which may represent a promising druggable host target [ 136 ]. Peripherin, like all type III intermediate filament proteins, does not possess signals for cell membrane recruitment, and the mechanism by which these proteins are transported to the cell surface is still unknown.…”

Role of Non-Coding RNA in Neurological Complications Associated With Enterovirus 71

“…For the second route, Chen et al ( Chen et al., 2007 ) reported that EV71 infected and entered the CNS through retrograde axonal transport at spinal motor nerves. Lim et al ( Lim et al., 2021 ) further showed that surface-expressed peripherin in motor neurons provides anchor points for EV71 and contributes to viral transmission, whereas intracellular peripherin modulates EV71 genome replication, resulting in CNS infection. In amyotrophic lateral sclerosis (ALS) patients, miR-105 and miR-9 mainly dominate peripherin expression in motor neurons by targeting the 3’UTR of peripheral mRNA ( Hawley et al., 2019 ); however, their effects on EV71 have not been explored.…”