Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection

Helene A. Haeberle, Carin Dürrstein, Peter Rosenberger, Yashoda Hosakote Madaiah, Johannes Kuhlicke, Volkhard A J Kempf, Roberto Garofalo, Holger K. Eitzschig

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Abstract

Background: Hypoxia-inducible factor 1 (HIF)-1α is a transcription factor that functions as master regulator of mammalian oxygen homeostasis. In addition, recent studies identified a role for HIF-1α as transcriptional regulator during inflammation or infection. Based on studies showing that respiratory syncytial virus (RSV) is among the most potent biological stimuli to induce an inflammatory milieu, we hypothesized a role of HIF-1as transcriptional regulator during infections with RSV. Methodology, Principal Findings: We gained first insight from immunohistocemical studies of RSV-infected human pulmonary epithelia that were stained for HIF-1Α. These studies revealed that RSV-positive cells also stained for HIF-1α, suggesting concomitant HIF-activation during RSV infection. Similarly, Western blot analysis confirmed an approximately 8-fold increase in HIF-1α protein 24 h after RSV infection. In contrast, HIF-1α activation was abolished utilizing UV-treated RSV. Moreover, HIF-α-regulated genes (VEGF, CD73, FN-1, COX-2) were induced with RSV infection of wild-type cells. In contrast, HIF-1α dependent gene induction was abolished in pulmonary epithelia following siRNA mediated repression of HIF-1α. Measurements of the partial pressure of oxygen in the supernatants of RSV infected epithelia or controls revealed no differences in oxygen content, suggesting that HIF-1" activation is not caused by RSV associated hypoxia. Finally, studies of RSV pneumonitis in mice confirmed HIF-α-activation in a murine in vivo model. Conclusion/Significance: Taking together, these studies suggest hypoxia-independent activation of HIF-1α during infection with RSV in vitro and in vivo.

Original languageEnglish (US)
Article numbere3352
JournalPLoS One
Volume3
Issue number10
DOIs
StatePublished - Oct 7 2008

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Haeberle, H. A., Dürrstein, C., Rosenberger, P., Hosakote Madaiah, Y., Kuhlicke, J., Kempf, V. A. J., Garofalo, R., & Eitzschig, H. K. (2008). Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS One, 3(10), [e3352]. https://doi.org/10.1371/journal.pone.0003352