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

• Published in: PloS one Vol. 3; no. 10; p. e3352
• Main Authors: Haeberle, Helene A, Dürrstein, Carin, Rosenberger, Peter, Hosakote, Yashoda M, Kuhlicke, Johannes, Kempf, Volkhard A J, Garofalo, Roberto P, Eltzschig, Holger K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.10.2008; Public Library of Science (PLoS)
• Subjects: Anesthesiology; Anesthesiology and Pain Management/Perioperative Critical Care; Animals; Bacterial infections; Biochemistry/Transcription and Translation; Blood Gas Analysis; Blotting, Western; Cancer; CD73 antigen; Cell Biology/Cell Signaling; Cell Line; Critical Care and Emergency Medicine/Pediatric Critical Care; Critical Care and Emergency Medicine/Respiratory Failure; Cyclooxygenase-2; Enzyme-Linked Immunosorbent Assay; Female; Gene expression; Gene Expression Regulation - physiology; Genetics and Genomics/Gene Expression; Hepatitis; Homeostasis; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-Inducible Factor 1 - physiology; Hypoxia-inducible factors; Immunohistochemistry; Immunology/Genetics of the Immune System; Immunology/Immune Response; Immunology/Innate Immunity; In vivo methods and tests; Infections; Infectious Diseases/Respiratory Infections; Infectious Diseases/Viral Infections; Inflammation; Inflammatory bowel disease; Intensive care; Medicine; Metabolism; Mice; Mice, Inbred BALB C; Microbiology/Immunity to Infections; Microbiology/Innate Immunity; Oxygen; Oxygen - blood; Oxygen - metabolism; Oxygen content; Partial pressure; Pediatrics; Physiology; Pneumonitis; Protein folding; Proteins; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Rodents; siRNA; Studies; Toxoplasma gondii; Transcription factors; Vascular endothelial growth factor; Viral infections; Virology/Animal Models of Infection; Virology/Effects of Virus Infection on Host Gene Expression; Viruses; United States > US; Texas; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003352

Hypoxia-inducible factor 1 (HIF)-1alpha is a transcription factor that functions as master regulator of mammalian oxygen homeostasis. In addition, recent studies identified a role for HIF-1alpha 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-1alpha as transcriptional regulator during infections with RSV. We gained first insight from immunohistocemical 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 24 h after RSV infection. In contrast, HIF-1alpha activation was abolished utilizing UV-treated RSV. Moreover, HIF-alpha-regulated genes (VEGF, CD73, FN-1, COX-2) were induced with RSV infection of wild-type cells. In contrast, HIF-1alpha 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 or controls revealed no differences in oxygen content, suggesting that HIF-1alpha activation is not caused by RSV associated hypoxia. Finally, studies of RSV pneumonitis in mice confirmed HIF-alpha-activation in a murine in vivo model. Taking together, these studies suggest hypoxia-independent activation of HIF-1alpha during infection with RSV in vitro and in vivo.