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 IFNb 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.

MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

“…However, MLV suppresses the activation of ISG15 and ISG56 induced by IFNs in MARC-145 cells, implying that other mechanisms might contribute to the impairment of IFN-I signaling during PRRSV infection (43). Cellular miRNAs were shown to be used by viruses to evade IFN-I-mediated antiviral responses in host cells (18,21,44,45). However, whether miRNAs participate in PRRSV-mediated evasion of IFN-I-mediated antiviral responses remains elusive.…”

“…A series of assays was performed to monitor the activation of NF-kB, IRFs, IFN-a promoter, IFN-b promoter, and ISRE after stimulating with poly(I:C). miR-146a was shown to suppress NF-kB activation (18)(19)(20), whereas miR-155 was demonstrated to promote IFN-I signaling (23). Thus, we used these two miRNAs as controls.…”

“…It is not surprising that viruses can take advantage of host miRNAs that act as suppressors of IFN-I production to generate a suitable environment for their replication. Such miRNAs include the well-characterized miR-146a (18)(19)(20), miR-21 (21), and miR-576-3p (22). The crucial antiviral effects of IFN-I are dependent on the activation of the JAK-STAT pathway (7).…”

Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

“…We also investigated changes in expression of TRAF6, IRAK1, and TLR4, which have been reported to be targets of miR-146a. [25][26][27][28][29] Of these, TRAF6 expression was higher in obstructed than in sham-operated kidneys, an increase significantly inhibited by miR-146a-PEI-NPs, but not by control-miR-PEI-NPs (Figure 11). The expression levels of IRAK1 and TLR4 were also higher in obstructed than in sham-operated kidneys, but these increases were not significantly inhibited by either miR-146a-PEI-NPs or control-miR-PEI-NPs.…”

“…[15][16][17][18]24 miR146a has been reported to inhibit inflammation by suppressing target mRNAs, such as those encoding tumor necrosis factor receptor-associated factor 6 (TRAF6), interleukin-1 receptor-associated kinase 1 (IRAK1), and Toll-like receptor 4 (TLR4), resulting in the inhibition of NF-κB in several organs. [25][26][27][28][29] Recently, miR-146a was reported to inhibit the TGF-β 1 -Smad signaling pathway by suppressing Smad4. 30 Increased miR-146a expression has been observed in kidney samples of diabetic nephropathy patients.…”