Abstract
BACKGROUND: An infection with hepatitis D virus (HDV) is considered the most extreme form of viral hepatitis. Infection with HDV elicits strong increases in inflammation and hepatic injury, therefore pushing liver cirrhosis and development of hepatocellular carcinoma (HCC). Despite this, little is known on how HDV influences the host-cell's equilibrium. As the pathogenesis is majorly driven by host-responses, a deep understanding is required in terms of how signalling cascades are modulated by the virus in order to identify targets for preventive and therapeutic strategies. Accordingly, this study aims to establish the kinome profile for HDAg-expressing and HDV-replicating cells which could serve as base for future research characterizing HDV-host interaction. METHODS: We performed kinome profiling in Huh7 cells ectopically expressing the two HDV protein isoforms S- and LHDAg or replicating HDV genomes. Significantly deregulated kinases were identified using an array-based screening. RESULTS: The different HDAg isoforms revealed a differential impact on the overall signalling landscape predominantly in nucleoplasm. Enrichment analyses indicated that HDAg and HDV-replication elicit kinomic changes overlapping with footprints of several diseases such as viral carcinogenesis and HCC. The responsible kinases therefore present promising targets of intervention. Moreover, pathways of innate immunity, inflammation, growth-factor-response yet also distinct modulatory signalling cascades were identified. Most prominently, the MAPK- and PI3K-Akt-cascades were affected by all experimental conditions. Within these cascades AKT1, GSK3A and PRKACA were identified as the most influential hits. A hierarchical pathway map of identified deregulated kinases indicated major changes in inflammatory processes, cell cycle control and metabolic control. CONCLUSIONS: A detailed analysis of the impact of HDV on the cellular kinome was established. Based on this, host-factors, single hits and even entire signalling cascades were identified. These advance understanding of HDV life cycle, and support development of novel therapeutics, yet also help to assess pathogenic processes.