Format

Send to

Choose Destination
Sci Immunol. 2017 Feb 10;2(8). pii: eaal2861. doi: 10.1126/sciimmunol.aal2861.

Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.

Author information

1
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
2
MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
3
MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.
4
University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
5
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.
6
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.
7
Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK.
8
Department of Medicine, University of Cambridge, Cambridge, UK.
9
Department of Medicine, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, UK.
10
Department of Physiology, Development and Neuroscience, University of Cambridge, UK.

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, both S. aureus and S. pneumoniae infections 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.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center