title: Hcmv-miR-UL112 attenuates NK cell activity by inhibition type I interferon secretion.
abstract: 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.
authors.affiliation: Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, Zhejiang, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, Zhejiang, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, Zhejiang, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of cardiovascular internal medicine, Zhoushan Hospital, Zhoushan, Zhejiang, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Shen
authors.affiliation: Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, Zhejiang, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, China. Electronic address: yxc6229@sina.com.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, Zhejiang, China. Electronic address: xuliyunhappy@126.com.
authors.forename: Liyun
authors.initials: L
authors.lastname: Xu
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D052118:Lysosomal-Associated Membrane Protein 1; D035683:MicroRNAs; C000599836:microRNA-UL112, human cytomegalovirus; D016899:Interferon-beta
keywords: Hcmv-miR-UL112; Immune evasion; NK cells; Type I interferons