Abstract
Enterovirus A71 (EV-A71) is the major cause of severe hand-foot-and-mouth diseases (HFMD), especially encephalitis and other nervous system diseases. EV-A71 capsid protein VP1 mediates virus attachment and is the important virulence factor in the EV-A71pathogenesis. In this study, we explored the roles of VP1 in the permeability of blood–brain barrier (BBB). Sera albumin, Evans blue, and dextran leaked into brain parenchyma of the 1-week-old C57BL/6J mice intracranially injected with VP1 recombinant protein. VP1 also increased the permeability of the brain endothelial cells monolayer, an in vitro BBB model. Tight junction protein claudin-5 was reduced in the brain tissues or brain endothelial cells treated with VP1. In contrast, VP1 increased the expression of virus receptor vimentin, which could be blocked with VP1 neutralization antibody. Vimentin expression in the VP1-treated brain endothelial cells was regulated by TGF-β/Smad-3 and NF-κB signal pathways. Moreover, vimentin over-expression was accompanied with compromised BBB. From these studies, we conclude that EV-A71 virus capsid protein VP1 disrupted BBB and increased virus receptor vimentin, which both may contribute to the virus entrance into brain and EV-A71 CNS infection.
Highlights
We demonstrated that VP1 may promote enterovirus A 71 (EV-A71) entrance via the increased blood–brain barrier (BBB) permeability and vimentin expression on BBB
In the infants with brain stem encephalitis, VP1 expression was recorded in brain tissues (Li et al 2015b)
Fluorescein isothiocyanate–dextran (FD4) and Evans blue in the brain parenchyma may indicate the BBB impairment (Saunders et al 2015)
Summary
Hand-foot-and-mouth disease (HFMD) caused by enterovirus A 71 (EV-A71) is usually self-limited (Xu et al 2010). The aseptic meningitis, brain stem encephalitis, and other nervous system diseases in the EV-A71 infected infants may be life-threatening (Gu et al 2017). Blood–brain barrier (BBB) protects central nervous system (CNS) from harmful pathogens in the blood. The access of EV-A71 into the CNS, except via retrograde axonal transport by nerves, most likely occurs through the BBB (Feng et al 2016). The mechanisms by which EV-A71 crossing the BBB and disseminating into brain parenchyma remain largely enigmatic (Denizot et al 2012)
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