The host microRNA miR-301a blocks the IRF1-mediated neuronal innate immune response to Japanese encephalitis virus infection

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Science Signaling  14 Feb 2017:
Vol. 10, Issue 466, pp. eaaf5185
DOI: 10.1126/scisignal.aaf5185

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Fighting flavivirus infection

Japanese encephalitis virus (JEV), which is related to the Zika, West Nile, and dengue viruses, targets the central nervous system, causing viral encephalitis. Because of the high mortality rate in JEV-infected individuals and the neurological damage that afflicts survivors, effective antiviral therapies are urgently needed. Hazra et al. found that JEV infection of mouse and human neuronal cells increased the abundance of the microRNA miR-301a, which inhibited the cells from producing type I interferons (IFNs), cytokines that are critical to the antiviral immune response. One of the targets of miR-301a is the transcription factor IRF1, which is required for the expression of genes encoding type I IFNs. Treating JEV-infected mice with an inhibitor of miR-301a restored IRF1 abundance and function and led to increased type I IFN production, decreased viral replication, and increased survival. Together, these data suggest that targeting miR-301a may be an effective therapy against JEV infection.


Effective recognition of viral components and the subsequent stimulation of the production of type I interferons (IFNs) is crucial for the induction of host antiviral immunity. The failure of the host to efficiently produce type I IFNs in response to infection by the Japanese encephalitis virus (JEV) is linked with an increased probability for the disease to become lethal. JEV is a neurotropic virus of the Flaviviridae family that causes encephalitis in humans. JEV infection is regulated by several host factors, including microRNAs, which are conserved noncoding RNAs that participate in various physiological and pathological processes. We showed that the JEV-induced expression of miR-301a led to inhibition of the production of type I IFN by reducing the abundances of the transcription factor IFN regulatory factor 1 (IRF1) and the signaling protein suppressor of cytokine signaling 5 (SOCS5). Mechanistically, induction of miR-301a expression during JEV infection required the transcription factor nuclear factor κB. In mouse neurons, neutralization of miR-301a restored the host innate immune response by enabling IFN-β production, thereby restricting viral propagation. Inhibition of miR-301a in mouse brain rescued the production of IRF1 and SOCS5, increased the generation of IFN-β, and reduced the extent of JEV replication, thus improving mouse survival. Thus, our study suggests that the JEV-induced expression of miR-301a assists viral pathogenesis by suppressing IFN production, which might be targeted by antiviral therapies.

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