Metabolic ‘De-Programming’ of Neutrophils Protects Against Fatal Bloodstream Fungal Infections in Kidney Disease

Abstract

Disseminated candidiasis (DC) 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 Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of 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-programed’ glucose metabolism and rescued ROS production and candidacidal function 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.

Keywords: Disseminated candidiasis, fungus, kidney disease, uremia, neutrophils, antifungal immunity, ROS, metabolism