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

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  • A A Roger Thompson
  • Fiona Murphy
  • J P Thomson
  • Helen M. Marriott
  • A Tavares
  • Joseph A Willson
  • L Williams
  • Amy Lewis
  • p Dos Santos Coelho
  • C Doherty
  • Emily Watts
  • A G Hameed
  • N Arnold
  • Julie A. Preston
  • Allan Lawrie
  • V Finisguerra
  • Massimiliano Mazzone
  • J Goveia
  • F Taverna
  • Peter Carmeliet
  • Simon J Foster
  • Edwin R. Chilvers
  • Andrew S. Cowburn
  • David H. Dockrell
  • Randall S Johnson

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http://immunology.sciencemag.org/lookup/doi/10.1126/sciimmunol.aal2861
Original languageEnglish
Article numbereaal2861
JournalScience Immunology
Volume2
Issue number8
Early online date10 Feb 2017
DOIs
Publication statusPublished - 10 Feb 2017

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-1 and neutrophil metabolism. The therapeutic implications of this work is that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.

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