Interference of HCV with anti-infectious and inflammatory effector systems of the host

• Antragsteller: Professor Dr. Johannes Georg Bode
• Fachliche Zuordnung: Gastroenterologie ; Immunologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 21644054

• Erstellungsjahr: 2016

Zusammenfassung der Projektergebnisse

The hepatitis C virus (HCV) is one of the leading causes for chronic liver diseases, affecting approximately 150 million people worldwide. HCV broadly interferes with inter- and intracellular signalling pathways of the host involved in regulation of antiviral immunity and inflammatory response as well as in regulation of endocytosis, cell growth, apoptotic cell death and differentiation. Thereby several signalling molecules of the host cell have been identified to be critical interaction partners for HCV proteins in order to subvert host antiviral effector mechanisms and to enable viral life cycle. Previous work from our group could demonstrated that HCV enhances basal as well as growth factor-inducible activation of Akt by NS3/4A-dependent cleavage of the T cell protein tyrosine phosphatase (TC- PTP) and that this activation is crucial for viral replication. Our own unpublished observations indicate that HCV sensitizes its host cell for epidermal growth factor (EGF)-inducible signal-transduction and also influences expression of the different ErbB receptor family members including EGFR (also designed as ErbB1), ErbB2, 3 and 4. Thereby, HCV induces the expression of the ErbB3 ligand neuregulin (Nrg)1 which mediates down-regulation of ErbB3 expression at transcript and protein levels, respectively. Down-regulation of ErbB3 in turn is accompanied by an enhanced surface expression of EGFR. It is likely that these changes are linked to the surprising observation that HCV not only modulates basal as well as the TNFα- or IL-1β-inducible chemokine expression, but also induces EGF expression, extends the spectrum of EGF target genes and converts EGF into a potent inducer of chemokine expression. It is well conceivable that this together with the enhanced sensitization and expression of the EGF receptor is relevant for the viral life cycle and results in an auto-/paracrine loop by which HCV modulates the intercellular communication of its host cell, the function of its host cells and possibly also its own life cycle.

Projektbezogene Publikationen (Auswahl)

• (2009) Interplay between host cell and hepatitis C virus in regulating viral replication. Biol Chem 390: 1013-1032
  Bode JG, Brenndörfer ED, Karthe J, and Häussinger D
  
• (2010) Anti tumor necrosis factor alpha treatment promotes apoptosis and prevents hepatocyte regeneration in a mouse model of chronic hepatitis C virus (HCV): a clue to its beneficial effects in HCV therapy. Hepatology 52: 1553-1563
  Brenndörfer ED, Weiland M, Frelin L, Derk E, Ahlén G, Jiao J, Bode JG, Sällberg M
  
• (2011) c-Src is required for complex formation between the hepatitis C virus encoded proteins NS5A and NS5B - a prerequisite for replication. Hepatology 53: 1127-1136
  Pfannkuche A, Büther K, Karthe J, Poenisch M, Bartenschlager R, Trilling M, Hengel H, Willbold D, Häussinger D, Bode JG
  
• (2012) Hepatitis C Virus Non-structural 3/4A Protein Interferes with Intrahepatic IFNγ Production. Gut 61: 589-596
  Brenndörfer ED, Brass A, Söderholm J, Frelin L, Aleman S, Bode JG, Sällberg M
  
• (2014) Cleavage of the T cell protein tyrosine phosphatase by the hepatitis C virus nonstructural 3/4A protease induces a Th1 to Th2 shift reversible by ribavirin therapy. J Immunol 192: 1671-1680
  Brenndörfer ED, Brass A, Karthe J, Ahlén G, Bode JG, Sällberg M