Return of the Neurotropic Enteroviruses: Co-Opting Cellular Pathways for Infection

Abstract

Enteroviruses are among the most common human infectious agents. While infections are often mild, the severe neuropathogenesis associated with recent outbreaks of emerging non-polio enteroviruses, such as EV-A71 and EV-D68, highlights their continuing threat to public health. In recent years, our understanding of how non-polio enteroviruses co-opt cellular pathways has greatly increased, revealing intricate host–virus relationships. In this review, we focus on newly identified mechanisms by which enteroviruses hijack the cellular machinery to promote their replication and spread, and address their potential for the development of host-directed therapeutics. Specifically, we discuss newly identified cellular receptors and their contribution to neurotropism and spread, host factors required for viral entry and replication, and recent insights into lipid acquisition and replication organelle biogenesis. The comprehensive knowledge of common cellular pathways required by enteroviruses could expose vulnerabilities amenable for host-directed therapeutics against a broad spectrum of enteroviruses. Since this will likely include newly arising strains, it will better prepare us for future epidemics. Moreover, identifying host proteins specific to neurovirulent strains may allow us to better understand factors contributing to the neurotropism of these viruses.

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Similar information to what has been said about the viruses above, accounts also for other RNA viruses, including various enteroviruses [ 170 , 171 , 172 , 173 , 174 , 175 ] and influenza viruses [ 106 , 176 , 177 , 178 ].…”

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): [ 159 , 160 , 161 ]. Enterovirus: [ 170 , 172 , 173 , 204 , 205 ]. Influenza virus: [ 176 , 177 , 178 , 206 , 207 ].…”

Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil

“…EVs enter host cells by binding to one or multiple receptors (e.g., ICAM-1, CAR, DAF, and CD155), followed by receptor-mediated endocytosis and RNA release [ 15 ]. EVs are responsible for a broad-spectrum of diseases, such as the common cold; hand, foot, and mouth disease; myocarditis; and upper and lower respiratory tract infection.…”

“…Although EV infections are mostly asymptomatic, these viruses can cause severe CNS disease, particularly aseptic meningitis (AM), acute flaccid paralysis (AFP), encephalitis, and acute flaccid myelitis (AFM) [ 16 ]. To gain access to the CNS, EVs must cross the blood–brain barrier (BBB), infecting brain endothelial cells or immune cells, using the latter as vehicles in a mechanism known as the “Trojan Horse” [ 15 , 17 , 18 ]. Additionally, EVs can spread via neuromuscular junctions from muscles to motor neurons through retrograde axonal transport [ 15 , 17 ].…”

“…To gain access to the CNS, EVs must cross the blood–brain barrier (BBB), infecting brain endothelial cells or immune cells, using the latter as vehicles in a mechanism known as the “Trojan Horse” [ 15 , 17 , 18 ]. Additionally, EVs can spread via neuromuscular junctions from muscles to motor neurons through retrograde axonal transport [ 15 , 17 ]. A recent review by Majer and colleagues [ 18 ] discussed the pathways exploited by the EVs to counteract the BBB and gain access into the CNS.…”