Epstein barr virus encodes miRNAs to assist host immune escape

He, Cong; Wu, Jiayi; Yang, Dazhi; Yi, Weihong

doi:10.7150/jca.42498

Cited by 19 publications

(17 citation statements)

References 91 publications

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“…A closer look at the literature shows that there is a network of identified EBV-encoded miRNAs and their regulated targets. The identified target genes are mainly located in adaptive and innate immunity and immune escape mechanisms (Albanese et al, 2017), what also corroborates our hypothesis that miRNAs interfere with type I IFN signaling as part of the innate immune escape during EBV infection (Gallo et al, 2020;Iizasa et al, 2020;Li et al, 2020). With our experiments shown in Figures 3 and 4 and documented in Supplementary Figures 3 and 4, we confirmed a number of host cell transcripts targeted by viral miRNAs, but we also identified several previously unknown effectors and their cellular transcripts (Fig.…”

Section: Discussionsupporting

confidence: 88%

Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus

Bouvet

Voigt

Tagawa

et al. 2020

Preprint

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Epstein-Barr virus (EBV), a human herpes virus, 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 of 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 pre-latent phase of infection. The presence of epigenetically naïve, 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 plasmacytoid 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 pre-latent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV.Author summaryAcute 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 which induce 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 encoded by Epstein-Barr virus (EBV) control over a dozen cellular genes that contribute to the anti-viral 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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Section: Discussionsupporting

confidence: 88%

Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus

Bouvet

Voigt

Tagawa

et al. 2020

Preprint

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“…MiRNAs play very important roles in modulating the immune response during viral infections. MiRNAs can repress gene expression by targeting host cellular RNAs or viral RNAs during infection 13‐15 . Furthermore, miRNAs have essential functions in a number of immune‐related diseases 11,18 .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, altered expression levels of miRNAs are also associated with various diseases 10,12 . Strikingly, recent studies have shown that miRNAs, as vital modulators, are also involved in the regulation of viral infection and host defense 13‐15 . For instance, previous data suggest that specific miRNAs in hepatitis B virus are associated with liver disease and that Epstein‐Barr virus‐encoded miRNAs collaborate to assist in host immune escape 13‐15 .…”

Section: Introductionmentioning

confidence: 99%

“…Strikingly, recent studies have shown that miRNAs, as vital modulators, are also involved in the regulation of viral infection and host defense 13‐15 . For instance, previous data suggest that specific miRNAs in hepatitis B virus are associated with liver disease and that Epstein‐Barr virus‐encoded miRNAs collaborate to assist in host immune escape 13‐15 . Therefore, existing results indicate that viral infection can affect host homeostasis by regulating miRNA expression and that altered expression of miRNAs can cause other genes to regulate the host immune response to viral infection.…”

Section: Introductionmentioning

confidence: 99%

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Differential microRNA expression in the peripheral blood from human patients with COVID‐19

et al. 2020

Clinical Laboratory Analysis

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164

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Introduction The coronavirus disease (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which play important roles in regulating gene expression and are also considered as essential modulators during viral infection. The aim of this study was to elucidate the differential expression of miRNAs in COVID‐19. Methods The total RNA was extracted and purified from the peripheral blood of ten patients with COVID‐19 and four healthy donors. The expression levels of various miRNAs were detected by high‐throughput sequencing, and correlation analysis was performed on the target genes that are primed by miRNAs. Key findings Compared with the healthy controls, 35 miRNAs were upregulated and 38 miRNAs were downregulated in the human patients with COVID‐19. The top 10 genes were listed below: hsa‐miR‐16‐2‐3P,hsa‐miR‐5695,hsa‐miR‐10399‐3P,hsa‐miR‐6501‐5P,hsa‐miR‐361‐3P,hsa‐miR‐361‐3p, hsa‐miR‐4659a‐3p, hsa‐miR‐142‐5p, hsa‐miR‐4685‐3p, hsa‐miR‐454‐5p, and hsa‐miR‐30c‐5p. The 10 genes with the greatest reduction were listed below: hsa‐miR‐183‐5p, hsa‐miR‐627‐5p, hsa‐miR‐941, hsa‐miR‐21‐5p, hsa‐miR‐20a‐5p, hsa‐miR‐146b‐5p, hsa‐miR‐454‐3p, hsa‐miR‐18a‐5p, hsa‐miR‐340‐5p, and hsa‐miR‐17‐5p. Remarkably, miR‐16‐2‐3p was the most upregulated miRNA, with a 1.6‐fold change compared to that of the controls. Moreover, the expression of miR‐6501‐5p and miR‐618 was 1.5‐fold higher in the COVID‐19 patients than in the healthy donors. Meanwhile, miR‐627‐5p was the most downregulated miRNA, with a 2.3‐fold change compared to that of the controls. The expression of other miRNAs (miR‐183‐5p, miR‐627‐5p, and miR‐144‐3p) was reduced by more than 1.3‐fold compared to that of the healthy donors. Cluster analysis revealed that all of the differentially expressed miRNA target genes were clustered by their regulation of cellular components, molecular functions, and biological processes. Importantly, peptidases, protein kinases, and the ubiquitin system were shown to be the highest enrichment categories by enrichment analysis. Conclusions The differential miRNA expression found in COVID‐19 patients may regulate the immune responses and viral replication during viral infection.

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“…Particular attention is paid to miR-BART5-3p, and miR-BART1-5p in EBVaGC [ 79 ], since they were found to bind and facilitate degradation of the important tumor suppressor P53 mRNA [ 80 ]. Besides, miR-BART1-5 and miR-BART9 are involved in cell growth and migration by inducing the reduction of important proteins like E-cadherin, which are necessary to maintain epithelial cell cohesion [ 81 , 82 ].…”

Section: Ebv Latency and Epigenetic Activitymentioning

confidence: 99%

Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

Brisotto

Repetto

et al. 2020

IJMS

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Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein–Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.

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Epstein barr virus encodes miRNAs to assist host immune escape

Cited by 19 publications

References 91 publications

Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus

Multiple viral microRNAs regulate interferon release and signaling early during infection with Epstein-Barr virus

Differential microRNA expression in the peripheral blood from human patients with COVID‐19

Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

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