Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells

Abstract

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation.

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

“…We previously reported NOTCH‐mediated modulation of inflammation in JEV‐infected microglial cells (Kumari et al . ). Several reports suggested that the NOTCH signaling pathway may cross‐talk with TLR signaling pathway to control inflammation (Hu et al .…”

“…NOTCH pathway involves inflammatory cytokine production upon JEV infection (Kumari et al . ). Let‐7a/b expression can induce TNFα in microglia (Lehmann et al .…”

“…Previously, we have identified several significant miRNAs that are differentially expressed during JEV infection in the microglial cells (Kumari et al . ). Among them, we choose miRNAs let‐7a and let‐7b for further studies because of the following reasons; (a) MiRNAs let‐7a/b , are the highly abundant regulator of gene expression in the CNS.…”

“…S1A) (Kumari et al . ). In the present study, we further explored the role of let‐7a and let‐7b in JEV pathogenesis.…”

Exploitation of microRNAs by Japanese Encephalitis virus in human microglial cells

“…In addition, several of the differentially expressed microRNAs were found common to the previous published reports for example, miR‐21, miR‐101‐3p, miR‐32‐5p, miR‐4695‐3p, miR‐432‐5p, miR‐205, miR‐450b‐3p, miR‐3613‐5p, miR‐190a, miR‐299‐5p, miR‐4286,miR‐1264, miR‐193a‐3p, miR‐138, miR‐3182, miR‐19a, miR‐1260b, miR‐3074, miR‐374b, miR‐588, miR‐597, miR‐487b, miR‐676, miR‐196a, miR‐539‐3p, miR‐802, miR‐629‐3p,miR‐301a‐3p, miR‐3156, miR‐222‐5p, and miR‐29b‐3p. Consequently, the previous and current study indicates that these microRNAs might be relevant to JEV infection in human microglial cells . Moreover, there are two pairs of microRNA and gene targets, which were consistent with the previous report .…”