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.
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DOI：
10.1128/mbio.03440-20
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发表时间：
2021-03-30
期刊：
影响因子：
6.4
通讯作者：
Hammerschmidt W
中科院分区：
文献类型：
--
作者：
Bouvet M;Voigt S;Tagawa T;Albanese M;Chen YA;Chen Y;Fachko DN;Pich D;Göbel C;Skalsky RL;Hammerschmidt W
所有有核细胞的急性抗病毒功能依赖于病毒感染触发的I型干扰素（IFN-I）途径。宿主反应包括对入侵病毒的感知，诱导IFN- i基因转录的特定转录因子的激活，不同类型IFN- i的分泌及其被异二聚体IFN-α/β受体识别，随后JAK/STAT信号通路的激活，以及许多IFN刺激基因（ISGs）的转录。eb病毒（EBV）是一种人类疱疹病毒，编码44种microrna (mirna)，这些microrna在EBV感染的细胞中调节许多具有各种功能的基因。已经鉴定出EBV mirna的多个靶基因，其中一些在适应性抗病毒免疫反应中起重要作用。利用EBV突变衍生物，我们发现了病毒mirna在控制人类原代成熟B细胞感染时多功能I型干扰素（IFN）反应中的其他作用。我们还发现，在我们的模型中，Epstein-Barr病毒编码的小rna （EBERs）和LF2（先前报道的在诱导或调节IFN- i通路中具有功能的病毒基因）对分泌的IFN-α的影响可以忽略不计，甚至相反。数据挖掘和Ago PAR-CLIP实验揭示了与I型IFN通路相关的EBV miRNA的十多个先前未表征的直接细胞靶标。我们还发现了eb病毒mirna在B细胞中的间接靶点，如TRL7和TLR9，在感染的潜伏前阶段。表观遗传上幼稚的、非cpg甲基化的病毒DNA的存在对于在EBV感染期间以tlr9依赖的方式诱导IFN-α分泌是必不可少的。在一项新建立的融合实验中，我们证实EBV病毒粒子进入浆细胞样树突状细胞（pDCs）的一个亚群，并确定这些被感染的pDCs是EBV感染的外周血单个核细胞中IFN-α的主要产生者。我们的研究结果表明，许多EBV编码的mirna调节新感染EBV的原代人B细胞在感染潜伏前阶段的I型IFN反应，并抑制pDCs遇到EBV时IFN-α的急性释放。
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). 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 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 prelatent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV.
影响因子：
6.7
作者：
Cavrois M;Neidleman J;Greene WC
通讯作者：
Greene WC