Hypoxia determines survival outcomes of bacterial infection through HIF-1α–dependent reprogramming of leukocyte metabolism

Thompson, A. A. Roger and Dickinson, Rebecca S. and Murphy, Fiona and Thomson, John P. and Marriott, Helen M. and Tavares, Adriana and Willson, Joseph and Williams, Lynne and Lewis, Amy and Mirchandani, Ananda and Coelho, Patricia Dos Santos and Doherty, Catherine and Ryan, Eilise and Watts, Emily and Morton, Nicholas M. and Forbes, Shareen and Stimson, Roland H. and Hameed, Abdul G. and Arnold, Nadine and Preston, Julie A. and Lawrie, Allan and Finisguerra, Veronica and Mazzone, Massimiliano and Sadiku, Pranvera and Goveia, Jermaine and Taverna, Federico and Carmeliet, Peter and Foster, Simon J. and Chilvers, Edwin R. and Cowburn, Andrew S. and Dockrell, David H. and Johnson, Randall S. and Meehan, Richard R. and Whyte, Moira K. B. and Walmsley, Sarah R. (2017) Hypoxia determines survival outcomes of bacterial infection through HIF-1α–dependent reprogramming of leukocyte metabolism. Science Immunology, 2 (8). ISSN 2470-9468 (https://doi.org/10.1126/sciimmunol.aal2861)

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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.

ORCID iDs

Thompson, A. A. Roger, Dickinson, Rebecca S., Murphy, Fiona ORCID logoORCID: https://orcid.org/0000-0001-7925-0632, Thomson, John P., Marriott, Helen M., Tavares, Adriana, Willson, Joseph, Williams, Lynne, Lewis, Amy, Mirchandani, Ananda, Coelho, Patricia Dos Santos, Doherty, Catherine, Ryan, Eilise, Watts, Emily, Morton, Nicholas M., Forbes, Shareen, Stimson, Roland H., Hameed, Abdul G., Arnold, Nadine, Preston, Julie A., Lawrie, Allan, Finisguerra, Veronica, Mazzone, Massimiliano, Sadiku, Pranvera, Goveia, Jermaine, Taverna, Federico, Carmeliet, Peter, Foster, Simon J., Chilvers, Edwin R., Cowburn, Andrew S., Dockrell, David H., Johnson, Randall S., Meehan, Richard R., Whyte, Moira K. B. and Walmsley, Sarah R.;
CORE (COnnecting REpositories)