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

Infection outcomes are regulated by neutrophil responses to oxygen and nutrient availability. Hypoxic immune cell conditioning Oxygen deficiency, or hypoxia, has been shown to alter immune cell function. However, how these hypoxia-induced immune cell changes affect the host response to bacterial infection has remained unclear. Now, Thompson et al. report that although acute hypoxia accentuated morbidity and mortality as a result of bacterial infection in mice, chronic hypoxia before infection could actually prevent these pathological responses. This hypoxic preconditioning reduced neutrophil glucose utilization, decreasing the related pathology. If these findings hold true in humans, they suggest that immune targeting could aid patients with systemic hypoxia and chronic infections such as adult respiratory distress syndrome or chronic obstructive pulmonary disease. 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.