Souradip Mallick, National Institute of Technology, Rourkela
Epstein-Barr virus(EBV) is a DNA virus that belongs in the γ-herpesvirus family that produces lifelong infection and severe diseases- Burkitt lymphoma(BL). The virus mainly affects immune-compromised individuals suffering from nasopharyngeal cancer, and post-transplant lymphoproliferative disease (PTLD).
The EBV genome encodes different classes of non-coding RNAs including two long non-coding RNAs, EBV-encoded small RNAs 1 and 2(EBER1 and 2), circular RNAs, and 44 mature microRNAs distributed in clusters along the genome. For infection, EBV must evade the activation of type-I interferons(IFN-I). IFN-I production and signaling is a two-part system at the center of innate antiviral immunity. Initially, specialized pattern recognition receptors(PRRs) detect pathogen-associated molecular patterns(PAMPs). EBV inefficiently fuses with pDCs, infected pDCs are the main producers of INF-α. PRR engagement triggers activation of specific transcription factors which then induce transcription of IFN-I genes leading to production and secretion of type-I IFNs. Secreted IFN-I binds to a single, heterodimeric IFN-α/β receptor(IFNAR) on mammalian cells which activates JAK/STAT signaling pathways and culminating with the transcription of many IFN-stimulated genes(ISGs). To confirm that EBV miRNAs indeed attenuate IFN-mediated activation of the JAK-STAT pathway, a STAT-responsive luciferase reporter harboring SIS-inducible elements(SIE) was tested in the presence of EBV miRNAs in 293T cells. Along with inhibition of JAK1 and IRF9, both miR-BART1 and miR-BART3 suppressed SIE reporter activity. These demonstrate that EBV-encoded miRNAs inhibit the expression of cellular genes involved at every step of the type-I IFN pathway.
The attachment of PRRs, TLR7, and TLR9 signal through the MyD88 adaptor protein activates the transcription factor, IRF7. Human B cells express IFI16, cGAS, and downstream signaling components necessary to induce type-I IFN; but B lymphocytes fail to recognize the presence of genomic EBV DNA through cGAS-STING. BZLF1 interferes with the dimerization of IRF7 and blocks STAT1 tyrosine phosphorylation. The EBV kinase BGLF4 impedes IRF3 activity, attenuating type-I IFN signaling. The phenotypes of primary immune cells with an EBV strain and its mutant derivatives that are based on the reconstituted wildtype EBV strain r_wt/B95.8 were studied. This EBV strain encodes all 25 pre-miRNAs that are processed into 44 mature viral miRNAs, the deletion of all miRNAs in r_ΔmiR leads to an increase in apoptosis of EBV infected primary B cells and thereby reduced numbers of cells presented in S-phase demonstrating that EBV-encoded miRNAs are involved in the regulation of cell cycle functions.
Hence EBV-encoded miRNAs regulate type-I IFN response in newly EBV infected primary human B cells in the pre-latent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV.
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Source- Mickael Bouvet, Stefanie Voigt, Takanobu Tagawa, Manuel Albanese, Yen-Fu Adam Chen, Yan Chen, Devin N Fachko, Dagmar Pich, Christine Goebel, Rebecca Skalsky, Wolfgang Hammerschmidt; Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus; doi: https://doi.org/10.1101/2020.12.03.393306
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