Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication
| Autor: | Marc P. Windisch, Volker Lohmann, Ralf Bartenschlager, Artur Kaul, Johanna Mazur, Lars Kaderali, Philippe Metz, Alessia Ruggieri, Michael Frese, Marco Binder, Martin Trippler, Ulf Zeuge, Eva Dazert |
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| Rok vydání: | 2012 |
| Předmět: |
Hepatitis C virus
Medizin Nitric Oxide Synthase Type II Hepacivirus Virus Replication medicine.disease_cause Tripartite Motif Proteins Interferon-gamma Interferon RNA interference Tumor Cells Cultured medicine Humans RNA Messenger Replicon Phospholipid Transfer Proteins Gene Hepatology biology Effector Intracellular Signaling Peptides and Proteins Interferon-alpha Membrane Proteins RNA-Binding Proteins virus diseases Nitric oxide synthase 2 Antigens Differentiation Virology Up-Regulation Gene Expression Regulation Viral replication Hepatocytes biology.protein RNA Interference Carrier Proteins medicine.drug |
| Zdroj: | Hepatology. 56:2082-2093 |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.25908 |
| Popis: | Persistent infection with hepatitis C virus (HCV) can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All current therapies of hepatitis C include interferon-alpha (IFN-α). Moreover, IFN-gamma (IFN-γ), the only type II IFN, strongly inhibits HCV replication in vitro and is the primary mediator of HCV-specific antiviral T-cell responses. However, for both cytokines the precise set of effector protein(s) responsible for replication inhibition is not known. The aim of this study was the identification of IFN-α and IFN-γ stimulated genes (ISGs) responsible for controlling HCV replication. We devised an RNA interference (RNAi)-based “gain of function” screen and identified, in addition to known ISGs earlier reported to suppress HCV replication, several new ones with proven antiviral activity. These include IFIT3 (IFN-induced protein with tetratricopeptide repeats 3), TRIM14 (tripartite motif containing 14), PLSCR1 (phospholipid scramblase 1), and NOS2 (nitric oxide synthase 2, inducible). All ISGs identified in this study were up-regulated both by IFN-α and IFN-γ, demonstrating a substantial overlap of HCV-specific effectors induced by either cytokine. Nevertheless, some ISGs were more specific for IFN-α or IFN-γ, which was most pronounced in case of PLSCR1 and NOS2 that were identified as main effectors of IFN-γ-mediated anti-HCV activity. Combinatorial knockdowns of ISGs suggest additive or synergistic effects demonstrating that with either IFN, inhibition of HCV replication is caused by the combined action of multiple ISGs. Conclusion: Our study identifies a number of novel ISGs contributing to the suppression of HCV replication by type I and type II IFN. We demonstrate a substantial overlap of antiviral programs triggered by either cytokine and show that suppression of HCV replication is mediated by the concerted action of multiple effectors. (HEPATOLOGY 2012;56:2082–2093) |
| Databáze: | OpenAIRE |
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