Abstract
Flavonoids are widely distributed natural products with broad biological activities. Apigenin is a dietary flavonoid that has recently been demonstrated to interact with heterogeneous nuclear ribonucleoproteins (hnRNPs) and interferes with their RNA editing activity. We investigated whether apigenin possessed antiviral activity against enterovirus-71 (EV71) infection since EV71 infection requires of hnRNP proteins. We found that apigenin selectively blocks EV71 infection by disrupting viral RNA association with hnRNP A1 and A2 proteins. The estimated EC50 value for apigenin to block EV71 infection was determined at 10.3 µM, while the CC50 was estimated at 79.0 µM. The anti-EV71 activity was selective since no activity was detected against several DNA and RNA viruses. Although flavonoids in general share similar structural features, apigenin and kaempferol were among tested compounds with significant activity against EV71 infection. hnRNP proteins function as trans-acting factors regulating EV71 translation. We found that apigenin treatment did not affect EV71-induced nucleocytoplasmic redistribution of hnRNP A1 and A2 proteins. Instead, it prevented EV71 RNA association with hnRNP A1 and A2 proteins. Accordingly, suppression of hnRNP A1 and A2 expression markedly reduced EV71 infection. As a positive sense, single strand RNA virus, EV71 has a type I internal ribosome entry site (IRES) that cooperates with host factors and regulates EV71 translation. The effect of apigenin on EV71 infection was further demonstrated using a bicistronic vector that has the expression of a GFP protein under the control of EV71 5′-UTR. We found that apigenin treatment selectively suppressed the expression of GFP, but not a control gene. In addition to identification of apigenin as an antiviral agent against EV71 infection, this study also exemplifies the significance in antiviral agent discovery by targeting host factors essential for viral replication.
Highlights
Hand, foot and mouth disease (HFMD) is an infectious disease predominantly caused by enterovirus 71 (EV71) and coxsackievirus A16 (CAV16) of the Picornaviridae family [1]
We investigated whether apigenin treatment affected heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2 redistribution by immunostaining studies since nucleocytoplasmic redistribution has been reported during EV71 infection [7]. hnRNP A1 and A2 proteins were detected mainly in the nuclei of uninfected or apigenintreated cells (Fig. 3A, 3B)
We showed that apigenin treatment disrupted viral RNA association with host trans-acting factors, representing a previously undescribed mechanism for apigenin antiviral activity against EV71 infection
Summary
Foot and mouth disease (HFMD) is an infectious disease predominantly caused by enterovirus 71 (EV71) and coxsackievirus A16 (CAV16) of the Picornaviridae family [1]. The symptoms are generally selflimited and do not need medications, but those by EV71 infection can have more severe complications, including pulmonary edema, aseptic meningitis or even death. FBP2 functions as a negative regulator and EV71 infection leads to cleavage of FBP2 and enhanced translation of the precursor peptide [8]. Both hnRNP A1 and K proteins have been shown to interact with the stem-loops in the 59-UTR of EV71 RNA and play an essential role in driving EV71 translation [7,9,10]. The anti-EV71 activity of kaempferol was attributed to its ability to alter the composition of IRES associated proteins [11], though no detailed mechanism has been delineated
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