title: Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon.
abstract: There are no antivirals or vaccines available to treat Enterovirus 71 (EV71) infections. Although the type I interferon response, elicited upon virus infection, is critical to establishing host antiviral innate immunity, EV71 fails to induce this response efficiently. Here we provide new insights into potential anti-EV71 therapy by showing that neutralization of EV71-induced miR-146a prevents death in mice by restarting the production of type I interferon. EV71 infection upregulates miR-146a, which targets IRAK1 and TRAF6 involved in TLR signalling and type I interferon production. We further identify AP1 as being responsible for the EV71-induced expression of miR-146a. Surprisingly, knocking out miR-146a or neutralizing virus-induced miR-146a by specific antagomiR restores expressions of IRAK1 and TRAF6, augments IFNβ production, inhibits viral propagation and improves survival in the mouse model. Our results suggest that enterovirus-induced miR-146a facilitates viral pathogenesis by suppressing IFN production and provide a clue to developing preventive and therapeutic strategies for enterovirus infections.
authors.affiliation: 1] Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan [2] NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Bing-Ching
authors.initials: BC
authors.lastname: Ho
authors.affiliation: Laboratory Animal Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.affiliation: 1] Section of Molecular Biology, Division of Biological Sciences, University of California-San Diego, La Jolla, California 92093, USA [2] Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute, New York, New York 10021, USA.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Lu
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute, New York, New York 10021, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rudensky
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Laboratory Animal Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Chang-Wu
authors.initials: CW
authors.lastname: Tsai
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Luan-Yin
authors.initials: LY
authors.lastname: Chang
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
authors.affiliation: 1] Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan [2] Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.affiliation: 1] Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan [2] Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Lee
authors.affiliation: 1] NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan [3] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: 1] Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan [2] NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan [3] Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004770:Enterovirus / Q000276:immunology / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D048029:TNF Receptor-Associated Factor 6; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse