Abstract
BackgroundJapanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis which is more prevalent in South and Southeast Asia. JEV is a neurotropic virus which infiltrates into the brain through vascular endothelial cells. JEV infects neurons and microglial cells which causes neuronal damage and inflammation. However, JEV also evades the cellular immune response to survive in host cells. Viruses are known to modulate the expression of microRNAs, which in turn modulate cellular immune response by targeting expression of antiviral genes. The aim of this study is to understand the anti-inflammatory role of miR-146a during JEV infection, which facilitates immune evasion.MethodsHuman brain microglial cells (CHME3) were infected by JEV: JaOArS982 and P20778 strain, and expression of miR-146a were analyzed. Overexpression and knockdown studies of miR-146a were done to see the effect on NF-κB pathway and antiviral Jak-STAT pathway. Regulatory role of miR-146a on expression of interferon-stimulated genes was determined by real-time PCR and luciferase assays.ResultsJEV infection elevated the expression of miR-146a in JaOArS982 strain which caused downregulation of TRAF6, IRAK1, IRAK2, and STAT1 genes. Exogenous overexpression of miR-146a led to suppression of NF-κB activation and abrogation of Jak-STAT pathway upon JEV infection which led to downregulation of interferon-stimulated genes (IFIT-1 and IFIT-2) and facilitated viral replication. JEV infection initially upregulated cytokine production and activated STAT1 activity but STAT1 levels reduced at later time point, which led to the downregulation of interferon-stimulated genes.ConclusionUpregulation of miR-146a by JEV JaOArS982 strain leads to suppression of NF-κB activity and disruption of antiviral Jak-STAT signaling which helps the virus to evade the cellular immune response. This effect of JEV infection on miR-146a expression was found to be strain specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0249-0) contains supplementary material, which is available to authorized users.
Highlights
Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus which belongs to the family flaviviridae
These genes encode for various adaptor proteins involved in NF-κB activation. miR-146a has been reported to target STAT1 gene which acts as a transcription factor for expression of interferonstimulated genes [22]. miR-146a is induced by NF-κB activation, where induction of miR-146a targets genes involved in NF-κB activation and forms a regulatory negative feedback loop in monocytes [23]. miR-146a was found to be overexpressed in Tregs and its deficiency led to disruption of immunological tolerance in mice [24]. miR-146a overexpression leads to suppression of cellular inflammatory response and decrease in cytokine secretion [25,26]
JEV infection downregulates TNF receptor-associated factor 6 (TRAF6), IL-1 receptor associated kinase-1 (IRAK1), and IRAK2 genes As JEV infection induced the expression of miR-146a in JaOArS982 strain, we focused on this strain for our downstream studies
Summary
Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus which belongs to the family flaviviridae. MiR-146a is a well-known anti-inflammatory microRNA which targets TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor associated kinase-1 (IRAK1) and IRAK 2 genes [20]. Viruses like DENV, CHIKV and VSV have been reported to overexpress miR-146a which helps the virus to shut down inflammatory responses of cell [19,20,21]. These genes encode for various adaptor proteins involved in NF-κB activation. The aim of this study is to understand the anti-inflammatory role of miR-146a during JEV infection, which facilitates immune evasion
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