gms | German Medical Science

21. Jahrestagung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI)

Deutsche Gesellschaft für Pädiatrische Infektiologie (DGPI)

25.04. - 27.04.2013, Würzburg

Highly pathogenic avian influenza viruses: distinct response mechanisms of innate immune cells lead to systemic spreading of infection and cytokine burst

Meeting Abstract

  • J. Friesenhagen - Hannover Medical School, Department of pediatric pulmonolgy, allergology and neonatology - Hannover, Deutschland
  • Y. Boergeling - University of Muenster, Institute of Molecular Virology - Muenster, Deutschland
  • M. Schmolke - University of Muenster, Institute of Molecular Virology - Muenster, Deutschland
  • E. Hrincius - University of Muenster, Institute of Molecular Virology - Muenster, Deutschland
  • C. Spiekermann - University of Muenster, Institute of Immunology - Muenster, Deutschland
  • S. Kirschnek - University of Freiburg, Institute of Medical Microbiology - Freiburg, Deutschland
  • S. Ludwig - University of Muenster, Institute of Molecular Virology - Muenster, Deutschland
  • J. Roth - University of Muenster, Institute of Immunology - Muenster, Deutschland
  • corresponding author presenting/speaker D. Viemann - Hannover Medical School, Department of pediatric pulmonolgy, allergology and neonatology - Hannover, Deutschland

Deutsche Gesellschaft für Pädiatrische Infektiologie. 21. Jahrestagung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI). Würzburg, 25.-27.04.2013. Düsseldorf: German Medical Science GMS Publishing House; 2013. Doc13dgpi07

doi: 10.3205/13dgpi07, urn:nbn:de:0183-13dgpi077

Veröffentlicht: 28. März 2013

© 2013 Friesenhagen et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Highly pathogenic avian influenza viruses (HPAIV) cause severe infections of humans, typically characterized by systemic spreading and cytokine burst. In our studies we were interested in the underlying mechanisms and set out to identify the cell types responsible for cytokine burst and failure of immune defense by analyzing the role of innate immune cells in the response to influenza virus infection. We infected endothelial cells (HUVEC), primary human blood monocytes and monocyte-derived macrophages with different influenza virus strains, namely a low pathogenic human influenza strain, A/PR8/34 (H1N1) and two highly pathogenic avian influenza viruses, A/FPV/Bratislava/79 (H7N7) and A/Thailand/1(KAN-1)/2004 (H5N1). In microarray studies we observed strong induction of cytokines and chemokines in HUVEC in response to H5N1-infection whereas we found a surprisingly low induction of pro-inflammatory and anti-viral genes in monocytes and macrophages.

Studying transcription factor profiles and using siRNA approaches, we could reveal two transcription factors leading to an H5N1-specifically induced gene induction pattern in HUVEC, HMGA1 and NFATC4. Furthermore, we could show a strong NF-κB-dependence of H5N1-induced gene expression in an IKK-mutant of HUVEC. Our results propose a strong contribution of the endothelium to overwhelming cytokine induction during H5N1 infection. Strikingly, we did not find expression of NF-κB-dependent pro-inflammatory genes in H5N1-infected monocytes but could identify another transcription factor, RORα, as mediator of immunosuppression in H5N1-infected monocytes. We were able to show coherence between NF-κB-inhibition and RORα-activation by using ER-Hoxb8-cells derived from fetal livers of RORα-knockout mice in which NF-κB is normally induced by viruses. We therefore postulate a cell-type-specific mechanism by which H5N1 succeeds to escape the first barrier of immune defense. Additionally, our studies in influenza-infected macrophages revealed a further mechanism of H5N1-induced immunosuppression. We could show that H5N1 leads to inhibition of inflammasome activation in macrophages by missing expression of viral protein M2.

Taken together, we present cell-type-specific mechanisms induced by H5N1 which enable the virus to inhibit inflammatory responses of monocytes and macrophages enabling the virus to spread systemically and induce cytokine burst after infecting the endothelium.