Personal tools

Information zum Seitenaufbau und Sprungmarken fuer Screenreader-Benutzer: Ganz oben links auf jeder Seite befindet sich das Logo der JLU, verlinkt mit der Startseite. Neben dem Logo kann sich rechts daneben das Bannerbild anschließen. Rechts daneben kann sich ein weiteres Bild/Schriftzug befinden. Es folgt die Suche. Unterhalb dieser oberen Leiste schliesst sich die Hauptnavigation an. Unterhalb der Hauptnavigation befindet sich der Inhaltsbereich. Die Feinnavigation findet sich - sofern vorhanden - in der linken Spalte. In der rechten Spalte finden Sie ueblicherweise Kontaktdaten. Als Abschluss der Seite findet sich die Brotkrumennavigation und im Fussbereich Links zu Barrierefreiheit, Impressum, Hilfe und das Login fuer Redakteure. Barrierefreiheit JLU - Logo, Link zur Startseite der JLU-Gießen Direkt zur Navigation vertikale linke Navigationsleiste vor Sie sind hier Direkt zum Inhalt vor rechter Kolumne mit zusaetzlichen Informationen vor Suche vor Fußbereich mit Impressum

Document Actions

Project D2 - Identification of target structures for hepatitis E and C therapy

PI

 

PI

 

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.

 

References D2: 1. Elgner et al. (2016) Biochem J 473 (2):145-55. 2. Elgner et al. (2016) J Virol 28;90(24): 11181 -11196. 3. Feld and Zeuzem et al. (2015) NEJM 373:2599-07. 4. Lange et al. (2014) J Immunol 192:6037-443. 5. Lange et al. (2014) J Virol 88:6519-23. 6. Medvedev et al. (2017) Cell Biol Toxicol 33(3):211-231. 7. Medvedev et al. (2017) Free Radic Biol Med 110:300-315. 8. Peiffer et al. (2015) Hepatology 62(4):791-8. 9. Peiffer et al. (2016) Hepatology 63(1):63-73. 10. Ren et al. (2016) J Virol 90(13):5989-6000. 11. Ren et al. (2017) Eur J Cell Biol 96(6):542-552. 11. Welsch and Lange et al. (2015) J Hepatol 62:779-84 2. 4. 5. 12. Zeuzem et al. (2014) NEJM 370:1604-14.