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R9AP is a functional receptor for Epstein-Barr virus infection in both epithelial cells and B cells

ABSTRACT: Epstein-Barr virus (EBV), also known as the first human tumor virus, is linked to nearly 200,000 new cancer cases and millions of non-malignant diseases per year. EBV infects both human epithelial cells and B cells, several virally encoded glycoproteins define tropism and mediate a complicated entry process. Here, we showed that R9AP silencing, genetic knockout or antibody blocking significantly inhibits EBV infection in both epithelial and B cells, while R9AP overexpression promoted EBV infection, establishing this protein as a previously unidentified, essential entry receptor for EBV. Mechanistically, R9AP directly binds to EBV glycoprotein gH/gL to mediate membrane fusion. Importantly, the interaction of R9AP with gH/gL was inhibited by the competition of AMMO1, a highly potent anti-gH/gL neutralizing antibody blocking EBV infection of both Epithelial cells and B cells. Further, treatment with an R9AP peptide encompassing the gH/gL binding site inhibited EBV infection in vitro and reduced viral loads in EBV infected humanized mice. Altogether, we proposed R9AP as the first characterized common cellular receptor for EBV infection of the major cell types and could serve as a potential target for novel interventional strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159958 | GEO | 2021/01/31

REPOSITORIES: GEO

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Project description:Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix proteins deposition. Epstein - Barr virus (EBV) has previously been localised to alveolar epithelial cells of IPF patients. In this study we utilised a microarray based differential gene expression analysis strategy to identify potential molecular drivers of EBV associated lung fibrosis. We employed an alveolar epithelial cell line infected with EBV (A-Akata). Lytic phase infection induced in the A-Akata cells by TPA/BA treatment resulted in increase of TGFbeta1 and TIEG1 mRNA expression. Treatment of the A-Akata cells with ganciclovir,; resulted in a down regulation of both TIEG1 and TGFbeta1 expression, accompanied by a suppression of the EBV early response genes, Rta and Zta. This suppression of cell turnover mediators was correlated with an increase in cell activity index. To identify a possible role for Rta in driving apoptotic gene expression, we inhibited the Rta gene expression by silencing RNA, resulting in a decrease in TGFbeta1 and TIEG1 expression. This study identifies an apoptotic role of the EBV early response genes, as enhancer factors of TIEG1 and TGFbeta1 in EBV infected alveolar epithelial cells, potentially providing a possible mechanism for the role of EBV infection in pulmonary fibrosis. Experiment Overall Design: RNA isolation, cDNA synthesis, in vitro transcription and microarray analysis of A549, EBV infected A549 (AAKata) and A549 +TGFbeta1 10ng/ml 4hours were performed as previously reported. All analysis were microarrayed in duplicate. Image files were obtained through Affymetrix GeneChip software (MAS5). Subsequently robust multichip analysis (RMA) was performed. Expression data was compared to control by ANOVA analysis, p<0.05 correlated values and a signal log ratio of 0.6 or greater (equivalent to a fold change in expression of 1.5 or greater) were taken to identify significant differential regulation. All the SLRs data resulting from the comparative analyses were reported in a graph to determine the reliability of the assay and the linearity by r2. For all the microarray assays r2 value was higher than 0.98. Using gene expression values normalised by RMA, Average Linkage Hierarchical Cluster Analysis was performed and the results visualized by TreeView software.

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R9AP is a functional receptor for Epstein-Barr virus infection in both epithelial cells and B cells

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