Hyperglycemia supports ineffective inflammation by neutrophils during staphylococcal infection 2801

Abstract Description Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and the inability to regulate insulin. While the advent of insulin treatment has prolonged the lifespan of diabetic patients, the altered metabolic state can lead to a plethora of other complications, one of them being a heightened susceptibility to chronic infections most commonly by Staphylococcus aureus. Previous studies identify that diminished insulin signaling dampens macrophage effector functions despite heightened levels of exogenous glucose. In contrast, we identify in the streptozotocin model of diabetes that hypoinsulinemia has minimal effect on neutrophil metabolism and that the increased availability to glucose enhances production of reactive oxygen species (ROS) and neutrophil extracellular trap release (NETosis). Despite the enhanced neutrophil effector functions, the increased availability of glucose renders S. aureus resistant to neutrophil antimicrobial activities and renders diabetic mice susceptible to bacteremia. These studies highlight the complexity of insulin and glucose regulation at the host-microbe interface and demonstrate that the metabolic perturbations associated with diabetes differentially affect innate immune cells during infection. Funding Sources Supported by UTK startup funds and NIH 1R35GM154838. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)