Abstract
Japanese Encephalitis virus (JEV) is a neurotropic ssRNA virus, belonging to the Flaviviridae family. JEV is one of the leading causes of the viral encephalitis in Southeast-Asian countries. JEV primarily infects neurons however, the microglial activation has been reported to further enhance the neuroinflammation and promote neuronal death. The PI3K/AKT pathway has been reported to play an important role in type-I interferon response via IRF3. Phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/AKT pathway, participates in microglial polarization and neuroinflammation. The microRNAs are small non-coding endogenously expressed RNAs, which regulate the gene expression by binding at 3′ UTR of target gene. The human microglial cells were infected with JEV (JaOArS982 strain) and up-regulation of microRNA; hsa-miR-374b-5p was confirmed by qRT-PCR. The genes in PI3K/AKT pathway, over-expression and knock-down studies of hsa-miR-374b-5p with and without JEV infection were analyzed through immuno blotting. The regulatory role of hsa-miR-374b-5p on the expression of type-I interferon was determined by luciferase assays. JEV infection modulated the expression of hsa-miR-374b-5p and PI3K/AKT pathway via PTEN. The over-expression of hsa-miR-374b-5p suppressed the PTEN while up-regulated the AKT and IRF3 proteins, whereas, the knockdown rescued the PTEN expression and suppressed the AKT and IRF3 proteins. The modulation of hsa-miR-374b-5p regulated the type-I interferon response during JEV infection. In present study, we have shown the modulation of PTEN by hsa-miR-374b-5p, which regulated the PI3K/AKT/IRF3 axis in JEV infected microglial cells.
Highlights
The Japanese Encephalitis virus (JEV) is a mosquito-borne Flavivirus belongs to Flaviviridae family
We demonstrated the suppression of Phosphatase and tensin homolog (PTEN) by microRNA, hsa-miR-374b-5p at 24 h of JEV infection in human microglial cells
We and others have previously reported the JEV infection in the brain resident macrophages (Thongtan et al, 2010; Manocha et al, 2014; Sharma et al, 2015; Lannes et al, 2017)
Summary
The Japanese Encephalitis virus (JEV) is a mosquito-borne Flavivirus belongs to Flaviviridae family. JEV has been reported to persist in microglial cells, which could be a plausible reservoir for infection (Thongtan et al, 2010). The JEV primarily infects and kills neurons and further enhances the neuroinflammatory events by producing chemokines and cytokines, which in turn activates microglial cells and leads to neuronal death in a bystander fashion (Ghoshal et al, 2007; Chen et al, 2010, 2012a). We and others have previously reported the perturbation in cellular microRNA expression patterns during JEV infection for the purpose of replication and immune evasion (Cullen, 2013; Sharma et al, 2015, 2016; Rastogi et al, 2018)
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