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Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.

ABSTRACT: Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed in wild type injected with HCV core protein into the hippocampus. In vitro analysis in neuronal cells exposed to HCV core demonstrated retraction of the neuronal processes in an ERK/Signal Transducer and Activator of Transcription 3 (STAT3)-dependent manner dependent on toll-like receptor 2 (TLR2) signaling activation. These results indicate that HCV core protein neurotoxicity may be mediated by the sustained activation of ERK/STAT3 via TLR2-IRAK1 signaling pathway. These pathways provide novel targets for development of neuroprotective treatments for HCV involvement of the CNS.

SUBMITTER: Paulino AD

PROVIDER: S-EPMC3919659 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.

Paulino Amy D AD Ubhi Kiren K Rockenstein Edward E Adame Anthony A Crews Leslie L Letendre Scott S Ellis Ronald R Everall Ian P IP Grant Igor I Masliah Eliezer E

Journal of neurovirology 20110610 4

Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed ...[more]

PMID: 21660601

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Project description:BackgroundInterleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. ?? T cells are an important innate source of IL-17. Both IL-17+ ?? T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.ObjectiveIn this study, we investigated the crosstalk between ?? T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ ?? T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.ResultsWe report here that IL-17+ ?? T cells but not naïve ?? T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of ?? T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of ?? T cells through IL-1? and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both ?? T cells and microglia, but did not require the expression of TLRs by ?? T cells. Similarly to cytokine-primed IL-17+ ?? T cells, IL-17+ ?? T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ ?? T cells required a direct cell-cell contact between T cells and neurons.ConclusionTaken together, these results point to a crucial role for microglia activated through TLRs in polarization of ?? T cells towards neurotoxic IL-17+ ?? T cells.

Project description:The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism.

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Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.

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Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.

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