Signalome-wide assessment of host cell response to hepatitis C virus

Gholamreza Haqshenas, Jianmin Wu, Kaylene J Simpson, Roger J. Daly, Hans J. Netter, Thomas F Baumert, Christian Doerig

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Host cell signalling during infection with intracellular pathogens remains poorly understood. Here we report on the use of antibody microarray technology to detect variations in the expression levels and phosphorylation status of host cell signalling proteins during hepatitis C virus (HCV) replication. Following transfection with HCV RNA, the JNK and NF-κ B pathways are suppressed, while the JAK/STAT5 pathway is activated; furthermore, components of the apoptosis and cell cycle control machineries are affected in the expression and/or phosphorylation status. RNAi-based hit validation identifies components of the JAK/STAT, NF-κ B, MAPK and calcium-induced pathways as modulators of HCV replication. Selective chemical inhibition of one of the identified targets, the JNK activator kinase MAP4K2, does impair HCV replication. Thus this study provides a comprehensive picture of host cell pathway mobilization by HCV and uncovers potential therapeutic targets. The strategy of identifying targets for anti-infective intervention within the host cell signalome can be applied to any intracellular pathogen.

Original languageEnglish
Article number15158
Number of pages11
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 8 May 2017

Keywords

  • cell signaling
  • hepatitis C virus

Cite this

Haqshenas, Gholamreza ; Wu, Jianmin ; Simpson, Kaylene J ; Daly, Roger J. ; Netter, Hans J. ; Baumert, Thomas F ; Doerig, Christian. / Signalome-wide assessment of host cell response to hepatitis C virus. In: Nature Communications. 2017 ; Vol. 8.
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abstract = "Host cell signalling during infection with intracellular pathogens remains poorly understood. Here we report on the use of antibody microarray technology to detect variations in the expression levels and phosphorylation status of host cell signalling proteins during hepatitis C virus (HCV) replication. Following transfection with HCV RNA, the JNK and NF-κ B pathways are suppressed, while the JAK/STAT5 pathway is activated; furthermore, components of the apoptosis and cell cycle control machineries are affected in the expression and/or phosphorylation status. RNAi-based hit validation identifies components of the JAK/STAT, NF-κ B, MAPK and calcium-induced pathways as modulators of HCV replication. Selective chemical inhibition of one of the identified targets, the JNK activator kinase MAP4K2, does impair HCV replication. Thus this study provides a comprehensive picture of host cell pathway mobilization by HCV and uncovers potential therapeutic targets. The strategy of identifying targets for anti-infective intervention within the host cell signalome can be applied to any intracellular pathogen.",
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Signalome-wide assessment of host cell response to hepatitis C virus. / Haqshenas, Gholamreza; Wu, Jianmin; Simpson, Kaylene J; Daly, Roger J.; Netter, Hans J.; Baumert, Thomas F; Doerig, Christian.

In: Nature Communications, Vol. 8, 15158, 08.05.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AB - Host cell signalling during infection with intracellular pathogens remains poorly understood. Here we report on the use of antibody microarray technology to detect variations in the expression levels and phosphorylation status of host cell signalling proteins during hepatitis C virus (HCV) replication. Following transfection with HCV RNA, the JNK and NF-κ B pathways are suppressed, while the JAK/STAT5 pathway is activated; furthermore, components of the apoptosis and cell cycle control machineries are affected in the expression and/or phosphorylation status. RNAi-based hit validation identifies components of the JAK/STAT, NF-κ B, MAPK and calcium-induced pathways as modulators of HCV replication. Selective chemical inhibition of one of the identified targets, the JNK activator kinase MAP4K2, does impair HCV replication. Thus this study provides a comprehensive picture of host cell pathway mobilization by HCV and uncovers potential therapeutic targets. The strategy of identifying targets for anti-infective intervention within the host cell signalome can be applied to any intracellular pathogen.

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