Research ArticleInfectious diseases

Restoring glucose uptake rescues neutrophil dysfunction and protects against systemic fungal infection in mouse models of kidney disease

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Science Translational Medicine  17 Jun 2020:
Vol. 12, Issue 548, eaay5691
DOI: 10.1126/scitranslmed.aay5691

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Uremia undermines antifungal immunity

Systemic fungal infections are more prevalent and difficult to treat in patients with kidney disease. Jawale et al. set out to discern the mechanisms responsible for this enhanced risk and identify a way to mitigate disseminated fungal infections in kidney disease. Using multiple mouse models of kidney disease, they observed that uremia specifically conferred enhanced susceptibility to Candida albicans, which is typically controlled by neutrophils. Uremia blunted reactive oxygen species generation by neutrophils through glucose uptake perturbation. Accordingly, neutrophils isolated from patients with kidney disease were more capable of controlling fungal growth in vitro after dialysis. GSK3β inhibition restored the defect in mice or in human neutrophils and represents a potential intervention for patients with chronic kidney disease.

Abstract

Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia; disseminated candidiasis fatality is twice as common in patients with uremia as those with normal kidney function. Many antifungal drugs are nephrotoxic, making treatment of these patients particularly challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here, we show in multiple models that uremic mice exhibit an increased susceptibility to systemic fungal infection. Uremia inhibits Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of GSK3β, resulting in reduced ROS generation and hence impaired killing of C. albicans in mice. Consequently, pharmacological inhibition of GSK3β restored glucose uptake and rescued ROS production and candidacidal function of neutrophils in uremic mice. Similarly, neutrophils isolated from patients with kidney disease and undergoing hemodialysis showed similar defect in the fungal killing activity, a phenotype rescued in the presence of a GSK3β inhibitor. These findings reveal a mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of disseminated candidiasis.

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