Thompson, A.A.R. orcid.org/0000-0002-0717-4551, Dickinson, R.S., Murphy, F. et al. (32 more authors) (2017) Hypoxia determines survival outcomes of bacterial infection through HIF-1α-dependent reprogramming of leukocyte metabolism. Science Immunology, 2 (8). ISSN 2470-9468
Abstract
Hypoxia and bacterial infection frequently coexist, 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 Staphylococcus aureus and Streptococcus pneumoniae infections rapidly induced progressive neutrophil-mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, before infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of hypoxia-inducible factor (HIF) pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilization, 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 after bacterial infection through suppression of HIF-1α and neutrophil metabolism. In the context of systemic or tissue hypoxia, therapies that target the host response could improve infection-associated morbidity and mortality.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Association for the Advancement of Science. This is an author produced version of a paper subsequently published in Science Immunology. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number ACADEMY OF MEDICAL SCIENCES UNSPECIFIED BRITISH HEART FOUNDATION FS/13/48/30453 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 15 Feb 2017 15:04 |
Last Modified: | 03 Nov 2017 16:46 |
Published Version: | https://doi.org/10.1126/sciimmunol.aal2861 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Refereed: | Yes |
Identification Number: | 10.1126/sciimmunol.aal2861 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:112265 |