Hcmv-miR-UL112 attenuates NK cell activity by inhibition type I interferon secretion
Hcmv-miR-UL112 attenuates NK cell activity by inhibition type I interferon secretion
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DOI：
10.1016/j.imlet.2014.12.003
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发表时间：
2015-02-01
影响因子：
4.4
通讯作者：
Xu, Liyun
中科院分区：
文献类型：
--
作者：
Huang, Yanyan;Chen, Dongdong;Xu, Liyun
病毒microRNAs （miRNAs）可以调节宿主的先天免疫反应。特别是人巨细胞病毒（HCMV） miRNA HCMV - mir - ul112通过下调宿主免疫基因和即时早期病毒基因表达逃避宿主免疫系统。自然杀伤细胞（NK）是重要的先天免疫细胞，具有强大的细胞毒性，在感染后被I型干扰素（ifn）激活。尽管宿主免疫系统具有强烈的拮抗作用，HCMV如何在宿主体内持续存在仍不清楚。采用慢病毒载体在外周血单核细胞（PBMCs）中稳定表达hcmv-miR-UL112。TaqMan miRNA法检测Hcmv-miR-UL112表达水平。采用CD107a动员试验和CytoTox 96非放射性细胞毒性试验评估hcmv-miR-UL112对NK细胞毒性的影响。采用酶联免疫吸附试验（ELISA）检测培养上清中I型IFNs的水平。为了证实I型IFN在hcmv- mir - ul112介导的NK细胞毒性中的作用，在lentii -hcmv- mir - ul112处理前，将PBMC与IFN受体拮抗抗体（IFNAR）孵育，并将重组I型IFN加入mir -转导的PBMC中。异位表达的hcmv-miR-UL112在功能上减弱NK细胞介导的细胞毒性，与I型IFN表达降低相关。转染hcmv - mir - ul112的细胞并没有比单独使用IFNAR中和单抗治疗进一步降低cd107的表达，并且加入重组I型IFN恢复了mir转导的PBMC中CD107a的表达。综上所述，我们的研究结果表明hcmv-miR-UL112通过下调I型IFN信号来抑制NK细胞的细胞毒性，从而破坏先天免疫。这些结果提供了一种新的基于mirna的免疫逃避机制，可能被HCMV利用。(C) 2014年欧洲免疫学会联合会。Elsevier B.V.版权所有。
Viral microRNAs (miRNAs) can regulate the host innate immune response. In particular, the human cytomegalovirus (HCMV) miRNA hcmv-miR-UL112 evades the host immune system by downregulating host immune gene and immediate-early viral gene expression. Natural killer (NK) cells are important innate immune cells with potent cytotoxicity, and are activated by type I interferons (IFNs) upon infection. It remains unclear how HCMV persists in the host despite the strongly antagonistic host immune system. A lentiviral vector was used to stably express hcmv-miR-UL112 in peripheral blood mononuclear cells (PBMCs). Hcmv-miR-UL112 expression levels were detected by TaqMan miRNA assay. The effects of hcmv-miR-UL112 on NK cell cytotoxicity were assessed with CD107a mobilization assay and CytoTox 96 non-radioactive cytotoxicity assay. Enzyme-linked immunosorbent assays (ELISA) were performed to detect type I IFNs levels in culture supernatants. To confirm the role of type I IFN in hcmv-miR-UL112-mediated NK cell cytotoxicity, PBMCs were incubated with antagonizing antibodies against IFN receptor (IFNAR) before lenti-hcmv-miR-UL112 treatment and recombinant type I IFN was added back into miR-transduced PBMC. Ectopically expressed hcmv-miR-UL112 functionally attenuated NK cell-mediated cytotoxicity, associated with decreased type I IFN expression. Hcmv-miR-UL112-transfected cells did not reduce the CD107-expression further than the IFNAR neutralizing mAbs-treatment alone, and adding back of recombinant type I IFN restored CD107a expression from the miR-transduced PBMC. Taken together, our results suggest that hcmv-miR-UL112 subverts innate immunity by downregulating type I IFN signaling to inhibit NK cell cytotoxicity. These results provide a new miRNA-based immunoevasion mechanism that may be exploited by HCMV. (C) 2014 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.