Untersuchungen zur Suppression der durch doppelsträngige RNA induzierten IFN-beta-Expression durch das Hepatitis A-Virus: Inhibition der RIG-I- und TLR3-vermittelten Signalwegezur Aktivierung des Transkriptionsfaktors IRF-3

The subject of this dissertation is the suppression of interferon-beta induction by hepatitis A virus (HAV), which is mediated by inhibition of activation of transcription factor IRF-3. In a first approach to localize the cellular target of HAV in the two dsRNA-induced signaling pathways leading to the activation of IRF-3, which are mediated by RIG-I and TLR3, respectively, nuclear translocation of IRF-3 was analyzed by using GFP-IRF-3, and poly(IC) transfection or NDV infection as activating stimuli. HAV efficiently suppressed transloaction of IRF-3, so the upstream cytoplasmic signaling pathway components were examined by reporter assays after overexpression, monitoring IFN-beta-enhancer and IRF-3-activation. It is demonstrated that HAV blocks the RIG-I-mediated pathway upstream of the IRF-3 kinases IKKe and TBK1 to block IFN-beta induction, and that HAV negatively affects the TLR3 pathway as well.