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

Abstract

Enterovirus 71 (EV71) is the main pathogenic virus that causes hand, foot, and mouth disease (HFMD). Studies have reported that EV71-induced infections including aseptic meningitis, acute flaccid paralysis, and even neurogenic pulmonary edema, can progress to severe neurological complications in infants, young children, and the immunosuppressed population. However, the mechanisms through which EV71 causes neurological diseases have not been fully explored. Non-coding RNAs (ncRNAs), are RNAs that do not code for proteins, play a key role in biological processes and disease development associated with EV71. In this review, we summarized recent advances concerning the impacts of ncRNAs on neurological diseases caused by interaction between EV71 and host, revealing the potential role of ncRNAs in pathogenesis, diagnosis and treatment of EV71-induced neurological complications.

Keywords: and mouse disease; enterovirus 71; foot; hand; long non-coding RNA; microRNA; non-coding RNA; virus-host interaction.

Figure 1

Role of ncRNAs in EV71 invasion through blood-brain barrier. (A) Direct invasion. miR-23b and miR-2911 downregulate junction protein claudin-5 and upregulate EV71 receptor vimentin, resulting in damage to blood-brain barrier and the attachment of EV71 through modulating VP1 expression. (B) Retrograde axonal transport. miR-105 and miR-9 can target peripherin, which facilitates EV71 attachment and replication, to modulate viral retrograde axonal transport. (C) “Trojan Horse” pathway. EV71 can hijack immune cells to intrude CNS, miR-3473a may mediate leukocyte trans-endothelial migration and induce BBB disruption associated with EV71. “*”: non-EV71-infected disease model.

Figure 2

Role of ncRNAs in central nervous system injury of EV71. EV71 injures CNS through direct damage by the virus and indirect injury mediated by immune and inflammatory responses. On the one hand, ncRNAs mediate direct injury of EV71 by modulating viral replication and host apoptosis. (A) miR-296-5p, miR-197 and miR-21 separately target viral genome, key host proteins and NF-κB pathway to involve in regulation of viral replication. (B) miR-16-5p and miR-494-3p respectively modulate cyclin expression and PI3K/Akt pathway to involve in regulation of host apoptosis. On the other hand, ncRNAs indirectly damage CNS through immunological concomitant inflammatory response and cytokines induction. (C) miR-30a promotes CNS damage by regulating immune and inflammatory responses, and (D) miR-124 upregulates the key pro-inflammatory cytokine, IL-6, aggravating damage induced by EV71. Red words indicate “upregulation”; green words indicate “downregulation”.

Figure 3

Role of ncRNAs in activation of NF-κB pathway with TLR signaling as an example. Toll-like receptors activate and recruit TIR-containing adaptor molecules, MyD88 and TRIF, which prime downstream effectors respectively, under the stimulation of signals such as LPS. Both of upstream signal paths finally transfer signals to IKKs, the protein kinase of IκB, and relieve inhibition of NF-κB. miR-628-5p, miR-21, miR-146a, miR-545 and miR-9-5p play an essential role in this process.