Abstract
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as master regulator of mammalian oxygen homeostasis. In addition, recent studies identified a role for HIF-1 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-1 as transcriptional regulator during infections with RSV. We gained first insight from immunohistochemical studies of RSV-infected human pulmonary epithelia that were stained for HIF-1alpha. These studies revealed that RSV-positive cells also stained for HIF-1alpha, suggesting concomitant HIF-activation during RSV infection. Similarly, Western blot analysis confirmed an approximately 8-fold increase in HIF-1alpha protein 24h after RSV infection. In contrast, HIF-1 activation was abolished utilizing UV-treated RSV. Moreover, HIF-regulated genes (VEGF, CD73, FN-1, COX-2) were induced with RSV infection of wildtype cells. In contrast, HIF-1 dependent gene induction was abolished in pulmonary epithelia following siRNA mediated repression of HIF-1alpha. Measurements of the partial pressure of oxygen in the supernatants of RSV infected epithelia showed 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-activation in a murine in vivo model. Taken together, these studies suggest oxygen-independent activation of HIF-1 during infection with RSV in vitro and in vivo.
Author and committee
dc:creator, dc:contributor.*- Author
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- Dürrstein, Carin
Identifiers
dc:identifier.*- Identifier
- hdl:10900/45383