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Bouvet, M. ; Voigt, S. ; Tagawa, T. ; Albanese, M. ; Chen, Y.-F. A. ; Chen, Y.* ; Fachko, D.N.* ; Pich, D. ; Göbel, C. ; Skalsky, R.L.* ; Hammerschmidt, W.

Multiple viral micrornas regulate interferon release and signaling early during infection with epstein-barr virus.

mBio 12:e03440-20 (2021)

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Epstein-Barr virus (EBV), a human herpesvirus, encodes 44 microRNAs (miRNAs), which regulate many genes with various functions in EBV-infected cells. Multiple target genes of the EBV miRNAs have been identified, some of which play important roles in adaptive antiviral immune responses. Using EBV mutant derivatives, we identified additional roles of viral miRNAs in governing versatile type I interferon (IFN) responses upon infection of human primary mature B cells. We also found that Epstein-Barr virus-encoded small RNAs (EBERs) and LF2, viral genes with previously reported functions in inducing or regulating IFN-I pathways, had negligible or even contrary effects on secreted IFN-α in our model. Data mining and Ago PAR-CLIP experiments uncovered more than a dozen previously uncharacterized, direct cellular targets of EBV miRNA associated with type I IFN pathways. We also identified indirect targets of EBV miRNAs in B cells, such as TRL7 and TLR9, in the prelatent phase of infection. The presence of epigenetically naive, non-CpG methylated viral DNA was essential to induce IFN-α secretion during EBV infection in a TLR9-dependent manner. In a newly established fusion assay, we verified that EBV virions enter a subset of plas-macytoid dendritic cells (pDCs) and determined that these infected pDCs are the primary producers of IFN-α in EBV-infected peripheral blood mononuclear cells. Our findings document that many EBV-encoded miRNAs regulate type I IFN response in newly EBV infected primary human B cells in the prelatent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV. IMPORTANCE Acute antiviral functions of all nucleated cells rely on type I interferon (IFN-I) pathways triggered upon viral infection. Host responses encompass the sensing of incoming viruses, the activation of specific transcription factors that induce the transcription of IFN-I genes, the secretion of different IFN-I types and their recognition by the heterodimeric IFN-α/β receptor, the subsequent activation of JAK/STAT signaling pathways, and, finally, the transcription of many IFN-stimulated genes (ISGs). In sum, these cellular functions establish a so-called antiviral state in infected and neighboring cells. To counteract these cellular defense mechanisms, viruses have evolved diverse strategies and encode gene products that target antiviral responses. Among such immune-evasive factors are viral microRNAs (miRNAs) that can interfere with host gene expression. We discovered that multiple miRNAs of Epstein-Barr virus (EBV) control over a dozen cellular genes that contribute to the antiviral states of immune cells, specifically B cells and plasmacytoid dendritic cells (pDCs). We identified the viral DNA genome as the activator of IFN-α and question the role of abundant EBV EBERs, that, contrary to previous reports, do not have an apparent inducing function in the IFN-I pathway early after infection.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords B Cells ; Epstein-barr Virus ; Immune Evasion ; Interferons ; Microrna ; Plasmacytoid Dendritic Cells; Plasmacytoid Dendritic Cells; Cytosolic Dna Sensor; Rig-i; Ebv Infection; Encoded Rnas; Responses; Protein; Mirnas; Gene; Identification

ISSN (print) / ISBN 2150-7511

e-ISSN 2150-7511

Journal mBio

Quellenangaben Volume: 12, Issue: 2, Article Number: e03440-20

Publisher American Society for Microbiology (ASM)

Publishing Place 1752 N St Nw, Washington, Dc 20036-2904 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Gene Vector (AGV)

Grants German Center for Infection Research
Deutsche Krebshilfe
Deutsche Forschungsgemeinschaft
NIH
European Molecular Biology Organization