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

Micro RNA s (mi RNA s) 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 mi RNA s over‐expressed 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 was previously reported to modulate inflammation in microglial cells through Toll‐like receptor 7 ( TLR 7) pathways; although 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 this end, we examined let‐7a/b and NOTCH signaling pathway in TLR 7 knockdown ( KD ) mice. We observed that TLR 7 KD or inhibition of let‐7a/b suppressed the JEV ‐induced NOTCH activation possibly via NF ‐κB dependent manner and subsequently, attenuated JEV ‐induced TNF α production in microglial cells. Furthermore, exosomes secreted from let‐7a/b over‐expressed microglia when transferred to uninfected mice brain induced caspase activation. Exosomes secreted from virus‐infected or let‐7a/b over‐expressed 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 mi RNA s in JEV pathogenesis. Let‐7a/b can interact with TLR 7 and NOTCH signaling pathway and enhance TNF α release from microglia. On the other hand, the exosomes secreted by JEV ‐infected microglia can activate caspases in uninfected neuronal cells which possibly contribute to bystander neuronal death.Cover Image for this issue: doi: 10.1111/jnc.14506 .