Presenting Author: Wonseok Choi
, Postdoctoral associate at Univ. of Pittsburgh
Abstract:
Neutrophils are critical for controlling systemic candidiasis (candidiasis), a bloodstream infection caused by Candida albicans. Neutrophils rely on extracellular glucose to fuel their antifungal activities at tissues. However, C. albicans consumes glucose, making it challenging for the neutrophils to survive and function at infected tissues. Hence, encountering fungal pathogens in glucose-depleted tissues exert metabolic challenges for neutrophils. It is unknown how neutrophils dynamically reprogram their metabolic pathways to function in glucose-deprived tissues in candidiasis. We show that neutrophils activate PYGL, an enzyme essential for the breakdown of intracellular glycogen storage to glucose, when glucose supply is limited. C. albicans regulate glycogenolysis in neutrophil in a dectin-1/Syk/Ca2+/PKA-axis dependent manner. Blockade of PYGL function in neutrophils inhibits fungicidal activities only when glucose availability is low and neutrophil specific PYGL ablated mice show increased susceptibility to candidiasis due to impaired ROS formation. Finally, treatment with β2-adrenergic receptor agonist, an approved drug and activator of PYGL function, improved antifungal activities of neutrophils in candidiasis. These results provide insights on how glycogenolysis supports compensatory metabolic reprograming required for antifungal function of neutrophils in the glucose-depleted infected tissues, a knowledge that can be therapeutically exploited by an approved drug.
Neutrophil specific glycogen metabolism supports antifungal function in the infected tissues
Category
Poster and Podium (Block Symposium)
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Date: May 5 Presentation Time: 11:30 AM to 12:45 PM Room: Exhibit Hall F1