title: H5N1 virus activates signaling pathways in human endothelial cells resulting in a specific imbalanced inflammatory response.
abstract: H5N1 influenza virus infections in humans cause a characteristic systemic inflammatory response syndrome; however, the molecular mechanisms are largely unknown. Endothelial cells (ECs) play a pivotal role in hyperdynamic septic diseases. To unravel specific signaling networks activated by H5N1 we used a genome-wide comparative systems biology approach analyzing gene expression in human ECs infected with three different human and avian influenza strains of high and low pathogenicity. Blocking of specific signaling pathways revealed that H5N1 induces an exceptionally NF-κB-dependent gene response in human endothelia. Additionally, the IFN-driven antiviral program in ECs is shown to be dependent on IFN regulatory factor 3 but significantly impaired upon H5N1 infection compared with low pathogenic influenza virus. As additional modulators of this H5N1-specific imbalanced gene response pattern, we identified HMGA1 as a novel transcription factor specifically responsible for the overwhelming proinflammatory but not antiviral response, whereas NFATC4 was found to regulate transcription of specifically H5N1-induced genes. We describe for the first time, to our knowledge, defined signaling patterns specifically activated by H5N1, which, in contrast to low pathogenic influenza viruses, are responsible for an imbalance of an overwhelming proinflammatory and impaired antiviral gene program.
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany. viemannd@uni-muenster.de
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
authors.forename: Mirco
authors.initials: M
authors.lastname: Schmolke
authors.forename: Aloys
authors.initials: A
authors.lastname: Lueken
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Boergeling
authors.forename: Judith
authors.initials: J
authors.lastname: Friesenhagen
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
mesh_terms: D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D020869:Gene Expression Profiling; D025741:HMGA1a Protein / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000254:growth & development / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D050839:Interferon Regulatory Factor-7 / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C494232:IRF3 protein, human; C494234:IRF7 protein, human; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D025741:HMGA1a Protein