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Nat Commun. 2017 May 8;8:15158. doi: 10.1038/ncomms15158.

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

Author information

Infection &Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Victoria 3800, Australia.
Kinghorn Cancer Centre &Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia.
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China.
Victorian Centre for Functional Genomics, The Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3052, Australia.
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia.
Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute, Melbourne Health, Victoria 3000, Australia.
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67091 Strasbourg, France.
Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.


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-κB 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-κB, 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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