Inhibition of p38 Mitogen-activated Protein Kinase Impairs Influenza Virus-induced Primary and Secondary Host Gene Responses and Protects Mice from Lethal H5N1 Infection*
| Autor: | Johannes Roth, Yvonne Börgeling, Carolin Nordhoff, Mirco Schmolke, Dorothee Viemann, Stephan Ludwig |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Influenza Virus Pyridines medicine.medical_treatment Influenza A Virus H7N7 Subtype STAT Transcription Factor Orthomyxoviridae Infections/enzymology/genetics/pathology/prevention & control Biochemistry p38 Mitogen-Activated Protein Kinases Madin Darby Canine Kidney Cells Mice Cytokines/biosynthesis/genetics Interferon Chlorocebus aethiops STAT1 Enzyme Inhibitors Phosphorylation Promoter Regions Genetic Imidazoles/pharmacology Enzyme Inhibitors/pharmacology Pyridines/pharmacology Regulation of gene expression JAK/STAT Signaling Mice Inbred BALB C biology Kinase Hypercytokinemia Imidazoles virus diseases Molecular Bases of Disease STAT1 Transcription Factor/genetics/metabolism P38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism Gene Expression Regulation/drug effects/genetics Cytokine STAT1 Transcription Factor Mitogen-activated protein kinase Cytokines Female medicine.drug MAP Kinase Signaling System p38 mitogen-activated protein kinases p38 MAPK Cercopithecus aethiops Microbiology Dogs Orthomyxoviridae Infections medicine Animals Humans Endothelium Protein kinase A Molecular Biology Vero Cells Highly Pathogenic Avian Influenza Virus (HPAIV) Phosphorylation/drug effects/genetics Influenza A Virus H5N1 Subtype MAP Kinase Signaling System/drug effects/genetics Cell Biology Interferon-beta Interferon-beta/biosynthesis/genetics Promoter Regions Genetic/genetics Influenza A Virus H5N1 Subtype/genetics/metabolism Gene Expression Regulation Immunology biology.protein |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry, Vol. 289, No 1 (2014) pp. 13-27 |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Early cytokine dysregulation upon infection with highly pathogenic avian influenza viruses (HPAIV) is a major determinant of viral pathogenicity. Results: p38 MAPK controls HPAIV-induced gene expression by regulating interferon synthesis and subsequently interferon signaling, whereas its inhibition protects mice from lethal infection. Conclusion: p38 MAPK is crucial for the induction of hypercytokinemia upon infection. Significance: Targeting p38 MAPK is a promising approach for antiviral intervention. Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. This cell-intrinsic hypercytokinemia seems to involve hyperinduction of p38 mitogen-activated protein kinase. Here we investigate the role of p38 MAPK signaling in the antiviral response against HPAIV in mice as well as in human endothelial cells, the latter being a primary source of cytokines during systemic infections. Global gene expression profiling of HPAIV-infected endothelial cells in the presence of the p38-specific inhibitor SB 202190 revealed that inhibition of p38 MAPK leads to reduced expression of IFNβ and other cytokines after H5N1 and H7N7 infection. More than 90% of all virus-induced genes were either partially or fully dependent on p38 signaling. Moreover, promoter analysis confirmed a direct impact of p38 on the IFNβ promoter activity. Furthermore, upon treatment with IFN or conditioned media from HPAIV-infected cells, p38 controls interferon-stimulated gene expression by coregulating STAT1 by phosphorylation at serine 727. In vivo inhibition of p38 MAPK greatly diminishes virus-induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show that p38 MAPK acts on two levels of the antiviral IFN response. Initially the kinase regulates IFN induction and, at a later stage, p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that protects mice from lethal influenza by suppressing excessive cytokine expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|