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RIPK3 Promotes JEV Replication in Neurons via Downregulation of IFI44L.

ABSTRACT: Japanese encephalitis virus (JEV), the leading cause of viral encephalitis in Asia, is neurovirulent and neuroinvasive. Neurons are the main target of JEV infection and propagation. Receptor interacting serine/threonine-protein kinase 3 (RIPK3) has been reported to contribute to neuroinflammation and neuronal death in many central nervous system diseases. In this study, we found that the progression of JE was alleviated in RIPK3-knockout (RIPK3-/-) mice in both peripheral and intracerebral infection. RIPK3-knockdown (RIPK3-RNAi) neuro2a cells showed higher cell viability during JEV infection. Moreover, the JEV load was significantly decreased in RIPK3-/- mouse-derived primary neurons and RIPK3-RNAi neuro2a cells compared with wild-type neurons, but this was not observed in microglia. Furthermore, RNA sequencing of brain tissues showed that the level of the interferon (IFN)-induced protein 44-like gene (IFI44L) was significantly increased in JEV-infected RIPK3-/- mouse brains, RIPK3-/- neurons, and RIPK3-RNAi-neuro2a cells. Then, it was demonstrated that the propagation of JEV was inhibited in IFI44L-overexpressing neuro2a cells and enhanced in IFI44L and RIPK3 double knockdown neuro2a cells. Taken together, our results showed that the increased expression of RIPK3 following JEV infection played complicated roles. On the one hand, RIPK3 participated in neuroinflammation and neuronal death during JEV infection. On the other hand, RIPK3 inhibited the expression of IFI44L to some extent, leading to the propagation of JEV in neurons, which might be a strategy for JEV to evade the cellular innate immune response.

SUBMITTER: Bian P

PROVIDER: S-EPMC7105639 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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RIPK3 Promotes JEV Replication in Neurons <i>via</i> Downregulation of IFI44L.

Bian Peiyu P Ye Chuantao C Zheng Xuyang X Luo Chuanyu C Yang Jiali J Li Mengyuan M Wang Yuan Y Yang Jing J Zhou Yun Y Zhang Fanglin F Lian Jianqi J Zhang Ying Y Jia Zhansheng Z Lei Yingfeng Y

Frontiers in microbiology 20200324

Japanese encephalitis virus (JEV), the leading cause of viral encephalitis in Asia, is neurovirulent and neuroinvasive. Neurons are the main target of JEV infection and propagation. Receptor interacting serine/threonine-protein kinase 3 (RIPK3) has been reported to contribute to neuroinflammation and neuronal death in many central nervous system diseases. In this study, we found that the progression of JE was alleviated in RIPK3-knockout (RIPK3<sup>-/-</sup>) mice in both peripheral and intracer ...[more]

PMID: 32265853

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Project description:Alphaviruses are enveloped, positive-sense RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) infects the neurons of rodents and is a model for studying factors that regulate infection of neuronal cells. The outcome of alphavirus infection of the central nervous system is dependent on neuronal maturation status. Differentiated mature neurons survive and control viral replication better than undifferentiated immature neurons. The cellular factors involved in age-dependent susceptibility include higher levels of antiapoptotic and innate immune factors in mature neurons. Because NF-?B pathway activation is required for the initiation of both apoptosis and the host antiviral response, we analyzed the role of NF-?B during SINV infection of differentiated and undifferentiated rat neuronal cells. SINV infection induced canonical NF-?B activation, as evidenced by the degradation of I?B? and the phosphorylation and nuclear translocation of p65. Inhibition or deletion of the upstream I?B kinase substantially reduced SINV replication in differentiated but not in undifferentiated neuronal cells or mouse embryo fibroblasts. NF-?B inhibition did not affect the establishment of infection, replication complex formation, the synthesis of nonstructural proteins, or viral RNA synthesis in differentiated neurons. However, the translation of structural proteins was impaired, phosphorylation of the ? subunit of eukaryotic translation initiation factor 2 (eIF2?) was decreased, and host protein synthesis was maintained, suggesting that NF-?B activation was involved in the regulation of translation during infection of mature neurons. Inhibition or deletion of double-stranded RNA-activated protein kinase (PKR) also decreased eIF2? phosphorylation, the translation of viral structural proteins, and virus production. Therefore, canonical NF-?B activation synergizes with PKR to promote SINV replication in differentiated neurons by facilitating viral structural protein translation.IMPORTANCE Mosquito-borne alphaviruses are a significant and growing cause of viral encephalomyelitis worldwide. The outcome of alphaviral neuronal infections is host age dependent and greatly affected by neuronal maturation status, with differentiated, mature neurons being more resistant to infection than undifferentiated, immature neurons. The biological factors that change during neuronal maturation and that influence the outcome of viral infection are currently only partially defined. These studies investigated the role of NF-?B in determining the outcome of alphaviral infection in mature and immature neurons. Inhibition of canonical NF-?B activation decreased alphavirus replication in mature neurons by regulating protein synthesis and limiting the production of the viral structural proteins but had little effect on viral replication in immature neurons or fibroblasts. Therefore, NF-?B is a signaling pathway that influences the maturation-dependent outcome of alphaviral infection in neurons and that highlights the importance of cellular context in determining the effects of signal pathway activation.

Project description:BackgroundIt is a basic task in high-throughput gene expression profiling studies to identify differentially expressed genes (DEGs) between two phenotypes. RankComp, an algorithm, could analyze the highly stable within-sample relative expression orderings (REOs) of gene pairs in a particular type of human normal tissue that are widely reversed in the cancer condition, thereby detecting DEGs for individual disease samples measured by a particular platform.MethodsIn the present study, Gene Expression Omnibus (GEO) Series (GSE) GSE75540, GSE138206 were downloaded from GEO, by analyzing DEGs in oral squamous cell carcinoma based on online datasets using the RankComp algorithm, using the Kaplan-Meier survival analysis and Cox regression analysis to survival analysis, Gene Set Enrichment Analysis (GSEA) to explore the potential molecular mechanisms underlying.ResultsWe identified 6 reverse gene pairs with stable REOs. All the 12 genes in these 6 reverse gene pairs have been reported to be associated with cancers. Notably, lower Interferon Induced Protein 44 Like (IFI44L) expression was associated with poorer overall survival (OS) and Disease-free survival (DFS) in oral squamous cell carcinoma patients, and IFI44L expression showed satisfactory predictive efficiency by receiver operating characteristic (ROC) curve. Moreover, low IFI44L expression was identified as risk factors for oral squamous cell carcinoma patients' OS. IFI44L downregulation would lead to the activation of the FRS-mediated FGFR1, FGFR3, and downstream signaling pathways, and might play a role in the PI3K-FGFR cascades.ConclusionsCollectively, we identified 6 reverse gene pairs with stable REOs in oral squamous cell carcinoma, which might serve as gene signatures playing a role in the diagnosis in oral squamous cell carcinoma. Moreover, high expression of IFI44L, one of the DEGs in the 6 reverse gene pairs, might be associated with favorable prognosis in oral squamous cell carcinoma patients and serve as a tumor suppressor by acting on the FRS-mediated FGFR signaling.

Dataset Information

RIPK3 Promotes JEV Replication in Neurons via Downregulation of IFI44L.

Publications

RIPK3 Promotes JEV Replication in Neurons <i>via</i> Downregulation of IFI44L.

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