Abstract
No effective drug is currently available for treatment of enterovirus 71 (EV71) infection. Schizonepeta tenuifolia Briq. (ST) has been used as a herbal constituent of traditional Chinese medicine. We studied whether the aqueous extract of Schizonepeta tenuifolia Briq (STE) has antiviral activity. STE inhibited replication of EV71, as evident by its ability to diminish plaque formation and cytopathic effect induced by EV71, and to inhibit the synthesis of viral RNA and protein. Moreover, daily single-dose STE treatment significantly improved the survival of EV71-infected mice, and ameliorated the symptoms. Mechanistically, STE exerts multiple effects on enteroviral infection. Treatment with STE reduced viral attachment and entry; the cleavage of eukaryotic translation initiation factor 4 G (eIF4G) by EV71 protease, 2Apro; virus-induced reactive oxygen species (ROS) formation; and relocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from the nucleus to the cytoplasm. It was accompanied by a decline in EV71-associated hyperphosphorylation of p38 kinase and EPS15. It is plausible that STE may inhibit ROS-induced p38 kinase activation, and subsequent hnRNP A1 relocation and EPS15-mediated membrane trafficking in infected cells. These findings suggest that STE possesses anti-EV71 activities, and may serve as health food or candidate antiviral drug for protection against EV71.
Highlights
Enterovirus 71 (EV71) is a non-enveloped, positive-sense single stranded RNA virus belonging to the family Picornaviridae, and is one of the major pathogens that causes hand, foot and mouth disease in young children, especially those under 5 years old[1]
rhabdomyosarcoma cells (RD) cells were infected with 100 plaque forming unit (PFU) of different enterovirus 71 (EV71) strains such as BrCr, 1743 and 4643, and overlaid with agarose containing 0, 625, or 1250 μg/ml of Schizonepeta tenuifolia Briq (STE)
The amounts of intracellular and extracellular viral particles decreased by more than 2 orders of magnitude in STE-treated infected cells, as compared to those of control treatment group (Fig. 1d). These findings demonstrate that STE possesses an anti-EV71 activity
Summary
Enterovirus 71 (EV71) is a non-enveloped, positive-sense single stranded RNA virus belonging to the family Picornaviridae, and is one of the major pathogens that causes hand, foot and mouth disease in young children, especially those under 5 years old[1]. Development of a specific anti-EV71 drug may improve the clinical outcomes in infected patients. Unlike cellular message RNA, the viral genomic RNA lacks the cap structure on 5′ end to recruit ribosome and initiate protein translation. The viral protease, 2Apro, hydrolyzes eukaryotic initiation factor 4G (eIF4G) and poly(A) binding protein (PABP) that are essential for the cap-dependent translation[16,17,18]. The antiviral capacity of tea polyphenols correlates with their antioxidant ability These studies suggest that the redox state of host is an important determinant of viral susceptibility, and that the antioxidative capacity of herbal extract partly accounts for the antiviral activity. Hsu et al showed that a 95% ethanolic extract of ST inhibits one out of four clinical isolated EV71 in a screen of anti-EV71 activity with Taiwanese folk medicinal plants. Lin et al showed that an aqueous extract of dried ST has no anti-EV71 activity among 22 antipyretic and toxin-eliminating traditional Chinese herbs[37]
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