Project D2 - Identification of target structures for hepatitis E and C therapy
- Project description
Background: Viruses, as obligatory parasites, need numerous host factors in order to replicate. Agents specifically directed against these host factors can develop an extraordinary antiviral effect. In contrast to antiviral substances specifically directed against viral target structures, those structures that have cellular factors as target structure are often effective against various viruses. This project focuses on the development of antiviral strategies against hepatitis C virus (HCV) and hepatitis E virus (HEV). HCV belongs to the family of flaviviruses. Despite efficient therapies that have been developed against HCV during the last few years, their availability is restricted. Therefore, exploring further therapeutic approaches makes sense, especially because of a multitude of closely related viruses of the family of flaviviruses such as dengue, Zika or yellow fever, which are currently not specifically treatable. In contrast to HCV, HEV is a non-enveloped capsid virus of the Hepeviridae family. At present, seven genotypes are described, of which genotypes 1-4 are capable of infecting humans. Whereas genotypes 1 and 2 infect humans only, types 3 and 4 have a zoonotic potential. A specific therapy against HEV infection does not exist.
In the course of the preparatory work, the influence of vitamin D receptor agonists on the HCV and HBV life cycle was characterized. By doing so, kinases being inhibited by calcitriol analogues could be identified. The inhibition of these kinases induced a strong antiviral effect against HCV. Likewise, structures of the autophagosomal system could also be identified as target structures for the inhibition of HCV release. In this context, in HCV-replicating cells the crosstalk between an increased ROS level, the inhibition of Nrf2/ARE-dependent gene expression, the induction of autophagy, and its relevance for virus release could be identified. In HEV-replicating cells, an increased ROS level could also be found, and the importance of the increased level for HEV release could be characterized. The exosomal structures play a crucial role in the HEV release of the infected cell. Based on this, HEV, which is a non-enveloped virus, is released in the form of exosomes as a so-called quasi-enveloped virus.
Scientific goals: By comparatively analyzing the kinomes of HCV and HEV-infected hepatoma cells as target structures, it is intended to characterize host kinases that are also responsible for the replication of distantly related virus families (e.g. HEV and HCV) and are suitable for pan-antiviral therapeutic goals. Furthermore, mechanisms leading to the increased ROS level in HEV-positive cells shall be characterized. The importance of the increased ROS level for the HEV-dependent induction of autophagy and the relevance of autophagy for the HEV life cycle shall be examined in detail, in particular regarding the exosomal release of HEV as a quasi-enveloped particle, in order to identify further target structures for antiviral substances inhibiting HEV replication.
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