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Receptors for enterovirus 71.

ABSTRACT: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

SUBMITTER: Yamayoshi S

PROVIDER: S-EPMC4126179 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Receptors for enterovirus 71.

Yamayoshi Seiya S Fujii Ken K Koike Satoshi S

Emerging microbes & infections 20140716 7

Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critica ...[more]

PMID: 26038749

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Project description:Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site.

Project description:We have previously shown that Heparin (Hep) significantly inhibited Enterovirus 71 (EV71) infection and binding in both Vero and a human neural cell line, SK-N-SH, in vitro. Therefore, in this study we intended to gain insight into the cellular and molecular mechanisms of action of Hep against clinical EV71 infection in SK-N-SH cells. Instead of stating a long list of gene functions and pathways, we tried to select for EV71-induced genes that were exclusively affected by antiviral activity of Hep through a multi-level comparison and characterization. Overall, our microarray analysis may suggest that Hep might exert its anti-EV71 activity in SK-N-SH cells, at least in part, through the following mechanisms: i. Reduction of the down-regulation effect of EV71 on TOX that would lead to an increased population of effective, mature T-cells and NK-cells; ii. Reduction of the up-regulation effect of EV71 on GIP, that in turn, would reduce recruiting different GPCRs, leading to a reduced viral infection in host cells; iii. Partially neutralization of the EV71-mediated apoptosis through expression of CARP2 that acts as an anti-apoptosis ubiquitin protein ligase (E3). EV71 is a neurovirological virus that can sometimes cause severe and fatal CNS complications in infected patients. Since still there is no approved drug for prophylaxis of EV71-casued disease, discovering a molecular drug target(s) for EV71 infection would be crucial. This was the first study to report direct assessment of mechanisms of action of antivirals against EV71 infection. SK-N-SH cells were infected with a clinical EV71 isolate followed by treatment with 125 µg/mL of Hep. At 72 hours post infection, antiviral activity and cytotoxicity of Hep at 125 µg/mL in 12-well plates were carried out at the same time as RNA extraction. This way, we could ensure that we would assess transcript profiles of the host cells under the same condition and time as assessment of antiviral activity and cytotoxicity for the same replicates. Changes in expression profiles of the host cells were comparatively assessed under four conditions: cell control (neither infection nor treatment, designated CC), treated only with Hep (compound control, designated Cyto), EV71-infected cells treated with Hep (treatment, designated H), and infected with EV71 without treatment with Hep (virus control, designated V). All experiments were applied in triplicate, and totally twelve GeneChip® Human Gene 1.0 ST arrays were purchased from Affymetrix and processed. Then, the following five contrasts were made: Hep vs. CC; VC vs. CC; Cyto vs CC; Hep vs. VC; and Hep vs. Cyto. For each contrast, only samples from the two target groups were included. The statistical parameters of ANOVAs, p values, multiple test corrections, and fold changes were calculated within each contrast. Then, a multi-level selection and analysis procedure was employed in order to attribute changes in the gene transcription level to antiviral activity of Hep.

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Receptors for enterovirus 71.

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Receptors for enterovirus 71.

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