Metabolic ‘de-programming’ of neutrophils protects against fatal bloodstream fungal infections during kidney disease

Abstract

Abstract Disseminated candidiasis (DC) is the third most common cause of mortality in hospital acquired infections. Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia. DC fatality is twice as common in patients with uremia as those without renal impairments. Many antifungal drugs are nephrotoxic, making treatment of these patients challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here we show that uremic mice show an increased susceptibility to DC. Uremia inhibits Glucose transporter 1 (Glut1)-mediated uptake of glucose in neutrophils by causing aberrant activation of Glycogen synthase kinase 3 beta (GSK3beta), resulting in reduced ROS generation and hence impaired killing of C. albicans in both mice and human cells. Consequently, pharmacological inhibition of GSK3beta ‘de-programs’ neutrophil function and restores glucose uptake, ROS production and candidacidal activity of neutrophils in uremic mice. These findings reveal a central mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of DC, with broader implications for other fatal systemic infections.