Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity

Combating fungal pathogens poses metabolic challenges for neutrophils, key innate cells in anti-Candida albicans immunity, yet how host-pathogen interactions cause remodeling of the neutrophil metabolism is unclear. We show that neutrophils mediate renal immunity to disseminated candidiasis by upregulating glucose uptake via selective expression of glucose transporter 1 (Glut1). Mechanistically, dectin-1-mediated recognition of beta-glucan leads to activation of PKC delta, which triggers phosphorylation, localization, and early glucose transport by a pool of pre-formed Glut1 in neutrophils. These events are followed by increased Glut1 gene transcription, leading to more sustained Glut1 accumulation, which is also dependent on the beta-glucan/dectin-1/CARD9 axis. Card9-deficient neutrophils show diminished glucose incorporation in candidiasis. Neutrophil-specific Glut1-ablated mice exhibit increased mortality in candidiasis caused by compromised neutrophil phagocytosis, reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. In human neutrophils, beta-glucan triggers metabolic remodeling and enhances candidacidal function. Our data show that the host-pathogen interface increases glycolytic activity in neutrophils by regulating Glut1 expression, localization, and function.

Automated summary

This study reveals the mechanism of metabolic remodeling in neutrophils during the immune response against fungal pathogens. Neutrophils upregulate glucose uptake by selectively expressing glucose transporter 1 (Glut1), which enhances their immune response against Candida albicans infection. The host-pathogen interaction also increases glycolytic activity in neutrophils through regulating Glut1 expression, localization, and function.