title: Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.
abstract: Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, bothS. aureusandS. pneumoniaeinfections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: A A R
authors.initials: AA
authors.lastname: Thompson
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Dickinson
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: F
authors.initials: F
authors.lastname: Murphy
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Thomson
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: H M
authors.initials: HM
authors.lastname: Marriott
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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authors.initials: A
authors.lastname: Tavares
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Willson
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: L
authors.initials: L
authors.lastname: Williams
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lewis
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mirchandani
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: P
authors.initials: P
authors.lastname: Dos Santos Coelho
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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authors.initials: C
authors.lastname: Doherty
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: E
authors.initials: E
authors.lastname: Ryan
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: E
authors.initials: E
authors.lastname: Watts
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: S
authors.initials: S
authors.lastname: Forbes
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: R H
authors.initials: RH
authors.lastname: Stimson
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Hameed
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: N
authors.initials: N
authors.lastname: Arnold
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Preston
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lawrie
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, B3000, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, B3000, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Finisguerra
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, B3000, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, B3000, Belgium.
authors.forename: M
authors.initials: M
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authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: P
authors.initials: P
authors.lastname: Sadiku
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, VIB, Leuven, B3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, K.U. Leuven, B3000, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, VIB, Leuven, B3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, K.U. Leuven, B3000, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Taverna
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, VIB, Leuven, B3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, K.U. Leuven, B3000, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Foster
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Chilvers
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Cowburn
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Dockrell
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.
authors.forename: R R
authors.initials: RR
authors.lastname: Meehan
authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: M K B
authors.initials: MK
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authors.affiliation: MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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authors.initials: SR
authors.lastname: Walmsley