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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0804198v1 183/8/5180    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Schmolke, M. Articles by Ludwig, S. PubMed PubMed Citation Articles by Schmolke, M. Articles by Ludwig, S.

Essential Impact of NF-B Signaling on the H5N1 Influenza A Virus-Induced Transcriptome¹

Mirco Schmolke,^* Dorothee Viemann, Johannes Roth, and Stephan Ludwig^2*

^*Institute of Molecular Virology, Center of Molecular Biology of Inflammation and Interdisciplinary Center of Medical Research and Institute of Immunology and Interdisciplinary Center of Medical Research, Universitaetsklinikum Muenster, Muenster, Germany

Systemic infections of humans and birds with highly pathogenic avian influenza A viruses of the H5N1 subtype are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm. Growing evidence supports the role of endothelial cells in these processes. The aim of this study was to elucidate determinants of this strong response in endothelial cells with a focus on the transcription factor NF-B. This factor is known as a major regulator of inflammatory response; however, its role in influenza virus replication and virus-induced immune responses is controversially discussed. By global mRNA profiling of infected cells in the presence or absence of a dominant negative mutant of IB kinase 2 that specifically blocks the pathway, we could show that almost all H5N1 virus-induced genes depend on functional NF-B signaling. In particular, activation of NF-B is a bottleneck for the expression of IFN-β and thus influences the expression of IFN-dependent genes indirectly in the primary innate immune response against H5N1 influenza virus. Control experiments with a low pathogenic influenza strain revealed a much weaker and less NF-B-dependent host cell response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (Lu477-11-2, SFB293 A17), the Interdisciplinary Clinical Research Centre of the University of Muenster (Grant Lud2/032/06), the "FluResearchNet" funded by the German Ministry of Education and Research, the European Commission funded Specific Targeted Research Project EUROFLU, and the VIRGIL European Network of Excellence on Antiviral Drug Resistance.

² Address correspondence and reprint requests to Dr. Stephan Ludwig, Institute of Molecular Virology, von Esmarch Strasse 56, 48149 Muenster, Germany. E-mail address: ludwigs{at}uni-muenster.de

³ Abbreviations used in this paper: HPAIV, highly pathogenic avian influenza virus; IRF, IFN regulatory factor; IKK2, IB kinase 2; ISRE, IFN-sensitive regulatory element; ISGF3, IFN-stimulated gene factor 3; ISG, IFN-stimulated gene; MxA, myxovirus resistance A; RIG-I, retinoic acid-induced gene I; EGFP, enhanced GFP; MOI, multiplicity of infection; GO, Gene Ontology; IP-10, IFN--inducible protein 10; NS1, nonstructural protein 1; HMEC-1, human microvascular endothelial cell 1; p.i., postinfection.

⁴ The online version of this article contains supplemental material.