Charakterisierung der Typ I IFN-antagonistischen Eigenschaften des Influenza B Virus
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Philipps-Universität Marburg
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Abstract
Expression of interferon (IFN)-alpha/beta in virus-infected vertebrate cells is a key event in the establishment of a sustained antiviral response, which is triggered by double-stranded (ds)RNA produced during viral replication. These antiviral cytokines initiate the expression of cellular proteins with activities that limit the replication and spread of the invading viruses. In this study we established and used a reverse genetic system for influenza B virus to demonstrate that the viral NS1 protein functions as the major viral IFN-antagonist and is necessary for efficient replication of influenza B virus. Characterization of the recombinant WT virus and the isogenic B/delNS1 virus that does not express the NS1 protein revealed that antagonization of the IFN-ß induction by the NS1 protein is due to its capacity to inhibit activation of the key transcription factor IRF-3. To test the postulate that the viral NS1 protein counteracts antiviral responses through sequestering intracellular dsRNA we analyzed a collection of recombinant influenza B viruses. As expected, viruses expressing dsRNA-binding defective NS1 proteins were strongly attenuated for replication in IFN-competent hosts, although they could effectively limit IFN induction. Interestingly, these virus mutants failed to prevent activation of the dsRNA-dependent protein kinase R (PKR), an important antiviral effector that can block the cellular translational machinery. Conversely, a mutant virus expressing the N-terminal dsRNA-binding domain of NS1 prevented PKR activation, but not IFN induction suggesting an important role of the NS1 C-terminal part for silencing the activation route of IFN-alpha/beta genes. Thus, our findings indicate an unexpected mechanistical dichotomy of the influenza B virus NS1 protein in the suppression of antiviral responses, which involves at least one activity that does not depend on dsRNA binding.
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Dates
Created: 2006Issued: 2006-09-08Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
PKRInterferonAngeborene ImmunitaetdsRNAInnate immunityPKRdsRNAInfluenza VirusInfluenza virus
DFG-subjects
Interferon
DDC-Numbers
610
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Dauber, Bianca Helene (13201551X): Charakterisierung der Typ I IFN-antagonistischen Eigenschaften des Influenza B Virus. : Philipps-Universität Marburg 2006-09-08. DOI: https://doi.org/10.17192/z2006.0575.
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This item has been published with the following license: In Copyright