Glycogen phosphorylase L confers metabolic flexibility in neutrophils to fight fungal infections in nutrient-deprived tissues.

Neutrophils are crucial for defense against systemic Candida albicans infections and rely on glucose for their antifungal functions, including the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). In infected tissues, glucose availability is limited due to fungal consumption, posing metabolic challenges for neutrophils. We demonstrate that neutrophils overcome glucose deprivation by activating the glycogen phosphorylase liver form (PYGL) enzyme, which mobilizes intracellular glycogen stores that fuel antifungal activity. Upon C. albicans infection, fungal sensing by dectin-1 and downstream signaling through Syk and protein kinase A (PKA) kinases drive glycogenolysis in neutrophils. Neutrophil-specific deletion of PYGL in mice increases susceptibility to candidiasis, associated with defective ROS and NET generation. Treatment with a β₂-adrenergic receptor agonist, a clinically approved PYGL activator, enhances host defense in candidiasis. These findings reveal a metabolic reprogramming mechanism that supports neutrophil function in nutrient-deprived environments and identify PYGL as a potential strategy to bolster antifungal defenses.