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J Neurochem. 2018 Dec 17. doi: 10.1111/jnc.14645. [Epub ahead of print]

Japanese Encephalitis Virus-induced let-7a/b interacted with the NOTCH-TLR7 pathway in microglia and facilitated neuronal death via caspase activation.

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National Brain Research Center, Manesar, India.
Translational Health Science and Technology Institute, Faridabad, India.
Regional Center for Biotechnology, Faridabad, India.


MicroRNAs (miRNAs) released from the activated microglia upon neurotropic virus infection may exacerbate the neuronal damage. Here, we identified let-7a and let-7b (let-7a/b) as one of the essential miRNAs overexpressed upon Japanese Encephalitis virus (JEV) infection and released in the culture supernatant of the JEV-infected microglial cells through extracellular vesicles. The let-7a/b were previously reported to modulate inflammation in microglial cells through Toll-like receptor 7 (TLR7) pathways; though their role in accelerating JEV pathogenesis remain unexplored. Therefore, we studied the role of let-7a/b in modulating microglia-mediated inflammation during JEV infection and investigated the effect of let-7a/b containing exosomes on primary neurons. To the end, we examined let-7a/b and NOTCH signaling pathway in TLR7 knockdown (KD) mice. We observed that TLR7 KD or inhibition of let-7a/b suppressed the JEV induced NOTCH activation possibly via NF-κB dependent manner and subsequently, attenuated JEV induced TNFα production in microglial cells. Further, exosomes secreted from let-7a/b overexpressed microglia when transferred to uninfected mice brain induced caspase activation. Exosomes secreted from virus-infected or let-7a/b overexpressed microglia when co-incubated with mouse neuronal (Neuro2a) cells or primary cortical neurons also facilitated caspase activation leading to neuronal death. Thus, our results provide evidence for the multifaceted role of let-7a/b miRNAs in JEV pathogenesis. Let-7a/b can interact with TLR7 and NOTCH signaling pathway and enhance TNFα release from microglia. On the other hand, exosomes secreted by JEV-infected microglia can activate caspases in uninfected neuronal cells which possibly contribute to bystander neuronal death. This article is protected by copyright. All rights reserved.


JEV ; MicroRNA; Neuroinflammation; exosome


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