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: 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, Sung-Liang Yu
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 3344 ( 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 24561744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Type I
• MicroRNAs
• Mirn146 microRNA, mouse
• TNF Receptor-Associated Factor 6
• Interleukin-1 Receptor-Associated Kinases
• Irak1 protein, mouse

Topics

• Animals
• Cell Death (drug effects, genetics)
• Cell Line, Tumor
• Enterovirus (immunology, pathogenicity)
• Enterovirus Infections (genetics, metabolism, prevention & control)
• Female
• Humans
• Immunohistochemistry
• Interferon Type I (metabolism)
• Interleukin-1 Receptor-Associated Kinases (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• TNF Receptor-Associated Factor 6 (genetics, metabolism)