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Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis.

ABSTRACT: Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.

SUBMITTER: Virzi A

PROVIDER: S-EPMC6938657 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis.

Virzì Alessia A Roca Suarez Armando Andres AA Baumert Thomas F TF Lupberger Joachim J

Cold Spring Harbor perspectives in medicine 20200102 1

Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especia ...[more]

PMID: 31501266

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Project description:Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from in vitro analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein.IMPORTANCE Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that this pathway is important for antiapoptotic and cell proliferation signaling. Blocking of endoglin-ALK1-SMAD1/5 might be a good candidate for therapy for liver cancer stem cells together with liver cirrhosis.

Project description:Background & aimsHepatitis B virus (HBV) RNA can undergo alternative splicing, but the relevance of this post-transcriptional regulation remains elusive. The mechanism of HBV alternative splicing regulation and its impact on liver pathogenesis were investigated.MethodsHBV RNA-interacting proteins were identified by RNA pull-down, combined with mass spectrometry analysis. HBV splicing regulation was investigated in chemically and surgically induced liver damage, in whole HBV genome transgenic mice and in hepatoma cells. Viral and endogenous gene expression were quantified by quantitative reverse transcription polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay. Resident liver immune cells were studied by fluorescence-activated cell sorting.ResultsHBV pregenomic RNA-interacting proteins were identified and 15% were directly related to the splicing machinery. Expression of these splicing factors was modulated in HBV transgenic mice with liver injuries and contributed to an increase of the HBV spliced RNA encoding for HBV splicing-generated protein (HBSP). HBSP transgenic mice with chemically induced liver fibrosis exhibited attenuated hepatic damage. The protective effect of HBSP resulted from a decrease of inflammatory monocyte/macrophage recruitment through downregulation of C-C motif chemokine ligand 2 (CCL2) expression in hepatocytes. In human hepatoma cells, the ability of HBSP to control CCL2 expression was confirmed and maintained in a whole HBV context. Finally, viral spliced RNA detection related to a decrease of CCL2 expression in the livers of HBV chronic carriers underscored this mechanism.ConclusionThe microenvironment, modified by liver injury, increased HBSP RNA expression through splicing factor regulation, which in turn controlled hepatocyte chemokine synthesis. This feedback mechanism provides a novel insight into liver immunopathogenesis during HBV infection. Lay summary: Hepatitis B virus persists for decades in the liver of chronically infected patients. Immune escape is one of the main mechanisms developed by this virus to survive. Our study highlights how the crosstalk between virus and liver infected cells may contribute to this immune escape.

Project description:Background & aimsThe hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown.MethodsInnate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage.ResultsThe 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity.ConclusionAntigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.

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Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis.

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Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis.

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