Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon

Bing-Ching Ho, I-Shing Yu, Li-Fan Lu, Alexander Rudensky, Hsuan-Yu Chen, Chang-Wu Tsai, Yih-Leong Chang, Chen-Tu Wu, Luan-Yin Chang, Shin-Ru Shih, Shu-Wha Lin, Chun-Nan Lee, Pan-Chyr Yang and Sung-Liang Yu ()
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Bing-Ching Ho: College of Medicine, National Taiwan University
I-Shing Yu: Laboratory Animal Center, National Taiwan University College of Medicine
Li-Fan Lu: Section of Molecular Biology, University of California-San Diego
Alexander Rudensky: Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute
Hsuan-Yu Chen: Institute of Statistical Science, Academia Sinica
Chang-Wu Tsai: Laboratory Animal Center, National Taiwan University College of Medicine
Yih-Leong Chang: National Taiwan University Hospital and National Taiwan University College of Medicine
Chen-Tu Wu: National Taiwan University Hospital and National Taiwan University College of Medicine
Luan-Yin Chang: National Taiwan University Hospital
Shin-Ru Shih: College of Medicine, Chang Gung University
Shu-Wha Lin: College of Medicine, National Taiwan University
Chun-Nan Lee: College of Medicine, National Taiwan University
Pan-Chyr Yang: NTU Center for Genomic Medicine, National Taiwan University College of Medicine
Sung-Liang Yu: College of Medicine, National Taiwan University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4344

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