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      Oxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection

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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-1α as 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-1α 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.

          Conclusions/Significance

          Taking together, these studies suggest hypoxia-independent activation of HIF-1α during infection with RSV in vitro and in vivo.

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          Most cited references60

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          HIF-1alpha is essential for myeloid cell-mediated inflammation.

          Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
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            HIF-1alpha expression regulates the bactericidal capacity of phagocytes.

            Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-alpha. Mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1alpha pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1alpha control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.
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              Hypoxia-inducible factor 1: master regulator of O2 homeostasis.

              Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates essential homeostatic responses to reduced O2 availability in mammals. Recent studies have provided insights into the O2-dependent regulation of HIF-1 expression, target genes regulated by HIF-1, and the effects of HIF-1 deficiency on cellular physiology and embryonic development.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                7 October 2008
                : 3
                : 10
                : e3352
                Affiliations
                [1 ]Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany
                [2 ]Medical Microbiology and Hygiene Department, University of Tübingen, Tübingen, Germany
                [3 ]Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America
                [4 ]Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Science Center, Denver, Colorado, United States of America
                University of Giessen Lung Center, Germany
                Author notes

                Conceived and designed the experiments: HAH HKE. Performed the experiments: HAH CD PR YMH JK RPG. Analyzed the data: CD. Contributed reagents/materials/analysis tools: HAH RPG. Wrote the paper: CD VAJK HKE.

                Article
                08-PONE-RA-05574R1
                10.1371/journal.pone.0003352
                2556398
                18839041
                8d39c0b3-ed3b-4fa4-88ba-73c06bd3bdd8
                Haeberle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 19 July 2008
                : 15 September 2008
                Page count
                Pages: 11
                Categories
                Research Article
                Biochemistry/Transcription and Translation
                Cell Biology/Cell Signaling
                Genetics and Genomics/Gene Expression
                Immunology/Genetics of the Immune System
                Immunology/Immune Response
                Immunology/Innate Immunity
                Microbiology/Immunity to Infections
                Microbiology/Innate Immunity
                Virology/Animal Models of Infection
                Virology/Effects of Virus Infection on Host Gene Expression
                Anesthesiology and Pain Management/Perioperative Critical Care
                Critical Care and Emergency Medicine/Pediatric Critical Care
                Critical Care and Emergency Medicine/Respiratory Failure
                Infectious Diseases/Respiratory Infections
                Infectious Diseases/Viral Infections

                Uncategorized
                Uncategorized

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