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

• Published in: Nature communications 2017-05, Vol.8 (1), p.15158-11, Article 15158
• Main Authors: Haqshenas, Gholamreza, Wu, Jianmin, Simpson, Kaylene J., Daly, Roger J., Netter, Hans J., Baumert, Thomas F., Doerig, Christian
• Format: Article
• Language: English
• Subjects: 13/89; 38/109; 38/61; 631/326/596/1905; 631/80/86; 82/1; 82/79; 96/95; Antibodies; Apoptosis; Cancer; Cell cycle; Genomes; Genomics; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis C; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C - virology; Host-Pathogen Interactions; Human health and pathology; Humanities and Social Sciences; Humans; Infections; Janus Kinases - genetics; Janus Kinases - metabolism; Kinases; Life Sciences; multidisciplinary; NF-kappa B - genetics; NF-kappa B - metabolism; Phosphorylation; Proteins; Science; Science (multidisciplinary); Signal Transduction; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Virus Replication; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15158

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. Development of antiviral strategies depends on an understanding of virus–host interactions. Here, using HCV, Haqshenas et al . show that antibody microarray combined with a targeted siRNA screen can be a powerful tool to identify cellular signalling pathways that are important for virus replication.