Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication

Philippe Metz, Eva Dazert, Alessia Ruggieri, Johanna Mazur, Lars Kaderali, Arthur Kaul, Ulf Zeuge, Marc Windisch, Martin Trippler, Volker Lohmann, Marco Binder, Michael Frese, Ralf Bartenschlager

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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
Original languageEnglish
Pages (from-to)2082-2093
Number of pages12
JournalJournal of Hepatology and Gastroenterology
Volume56
Issue number6
DOIs
Publication statusPublished - 2012

Fingerprint

Interferon Type I
Virus Replication
Hepacivirus
Interferon-gamma
Genes
Phospholipid Transfer Proteins
Antiviral Agents
Nitric Oxide Synthase Type II
Cytokines
Chronic Hepatitis
Hepatitis C
RNA Interference
Liver Cirrhosis
Hepatocellular Carcinoma
Proteins
Infection

Cite this

Metz, P., Dazert, E., Ruggieri, A., Mazur, J., Kaderali, L., Kaul, A., ... Bartenschlager, R. (2012). Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Journal of Hepatology and Gastroenterology, 56(6), 2082-2093. https://doi.org/10.1002/HEP.25908
Metz, Philippe ; Dazert, Eva ; Ruggieri, Alessia ; Mazur, Johanna ; Kaderali, Lars ; Kaul, Arthur ; Zeuge, Ulf ; Windisch, Marc ; Trippler, Martin ; Lohmann, Volker ; Binder, Marco ; Frese, Michael ; Bartenschlager, Ralf. / Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. In: Journal of Hepatology and Gastroenterology. 2012 ; Vol. 56, No. 6. pp. 2082-2093.
@article{cab4851c53eb4a0db0f2409d72707b73,
title = "Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication",
abstract = "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",
keywords = "hepatitis C virus, Interferon",
author = "Philippe Metz and Eva Dazert and Alessia Ruggieri and Johanna Mazur and Lars Kaderali and Arthur Kaul and Ulf Zeuge and Marc Windisch and Martin Trippler and Volker Lohmann and Marco Binder and Michael Frese and Ralf Bartenschlager",
year = "2012",
doi = "10.1002/HEP.25908",
language = "English",
volume = "56",
pages = "2082--2093",
journal = "Journal of Hepatology and Gastroenterology",
issn = "0270-9139",
publisher = "John Wiley & Sons",
number = "6",

}

Metz, P, Dazert, E, Ruggieri, A, Mazur, J, Kaderali, L, Kaul, A, Zeuge, U, Windisch, M, Trippler, M, Lohmann, V, Binder, M, Frese, M & Bartenschlager, R 2012, 'Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication', Journal of Hepatology and Gastroenterology, vol. 56, no. 6, pp. 2082-2093. https://doi.org/10.1002/HEP.25908

Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. / Metz, Philippe; Dazert, Eva; Ruggieri, Alessia; Mazur, Johanna; Kaderali, Lars; Kaul, Arthur; Zeuge, Ulf; Windisch, Marc; Trippler, Martin; Lohmann, Volker; Binder, Marco; Frese, Michael; Bartenschlager, Ralf.

In: Journal of Hepatology and Gastroenterology, Vol. 56, No. 6, 2012, p. 2082-2093.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication

AU - Metz, Philippe

AU - Dazert, Eva

AU - Ruggieri, Alessia

AU - Mazur, Johanna

AU - Kaderali, Lars

AU - Kaul, Arthur

AU - Zeuge, Ulf

AU - Windisch, Marc

AU - Trippler, Martin

AU - Lohmann, Volker

AU - Binder, Marco

AU - Frese, Michael

AU - Bartenschlager, Ralf

PY - 2012

Y1 - 2012

N2 - 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

AB - 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

KW - hepatitis C virus

KW - Interferon

U2 - 10.1002/HEP.25908

DO - 10.1002/HEP.25908

M3 - Article

VL - 56

SP - 2082

EP - 2093

JO - Journal of Hepatology and Gastroenterology

JF - Journal of Hepatology and Gastroenterology

SN - 0270-9139

IS - 6

ER -