Abstract
BackgroundNeuroinflammation associated with Japanese encephalitis (JE) is mainly due to the activation of glial cells with subsequent release of proinflammatory mediators from them. The recognition of viral RNA, in part, by the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) has been indicated to have a role in such processes. Even though neurons are also known to express this receptor, its role after JE virus (JEV) infections is yet to be elucidated.Methodology/Principal FindingsUpon infecting murine neuroblastoma cells and primary cortical neurons with JEV the expression profile of key proinflammatory cyto/chemokines were analyzed by qRT-PCR and bead array, both before and after ablation of RIG-I. Immunoblotting was performed to evaluate the levels of key molecules downstream to RIG-I leading to production of proinflammatory mediators. Changes in the intracellular viral antigen expression were confirmed by intracellular staining and immunoblotting. JEV infection induced neuronal expression of IL-6, IL-12p70, MCP-1, IP-10 and TNF-α in a time-dependent manner, which showed significant reduction upon RIG-I ablation. Molecules downstream to RIG-I showed significant changes upon JEV-infection, that were modulated following RIG-I ablation. Ablation of RIG-I in neurons also increased their susceptibility to JEV.Conclusions/SignificanceIn this study we propose that neurons are one of the potential sources of proinflammatory cyto/chemokines in JEV-infected brain that are produced via RIG-I dependent pathways. Ablation of RIG-I in neurons leads to increased viral load and reduced release of the cyto/chemokines.
Highlights
Japanese encephalitis (JE) is the cause of recurrent epidemic viral encephalitis in south-east Asia, with around 30,000–50,000 cases reported every year resulting in 10,000 to 15,000 deaths [1]
Conclusions/Significance: In this study we propose that neurons are one of the potential sources of proinflammatory cyto/ chemokines in JE virus (JEV)-infected brain that are produced via retinoic acid-inducible gene I (RIG-I) dependent pathways
Certain activated glial-derived factors contribute to tissue repair, the interactive cross-talk between neuronal injury and microglial activation often determine the neuropathological outcome in JEV infection
Summary
Japanese encephalitis (JE) is the cause of recurrent epidemic viral encephalitis in south-east Asia, with around 30,000–50,000 cases reported every year resulting in 10,000 to 15,000 deaths [1]. JEV is a neuroptropic virus that causes extensive neuronal death, which is reportedly mediated by activating the tumor necrosis factor receptor (TNFR)-1 complex [2]. Increased release of proinflammatory mediators like tumor necrosis factor (TNF)-a, IL-1b, IL-6, MCP-1 and RANTES have been observed from microglia activated by JEV infection [3,4,5]. This release of cyto/chemokines represent the innate immune response against flaviviral infection of brain which in turn, is known to be mediated by the pattern recognition receptors (PRRs) such as toll like receptors (TLRs) and RIG-I–like receptors (RLRs) [6]. Even though neurons are known to express this receptor, its role after JE virus (JEV) infections is yet to be elucidated
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