Glutathione reductase facilates immune defense against fungal infections

Abstract

Abstract Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, which plays an important role in Redox regulation. We expressed Gsr as a GST-fusion protein and produced a rabbit polyclonal antibody against Gsr. Using this antibody we examined Gsr expression levels in various mouse tissues. We found that Gsr was highly expressed in a variety of tissues, including lung, kidney, eyes, spleen, thymus, and bone marrow, while Gsr expression was very low in muscle and heart. Importantly, Gsr was not detected in any tissues of the Gsr hypomorphic mice. Because Gsr is expressed in lymphoid tissues and is implicated in phagocytic functions, we assessed the effect of Gsr deficiency on immune defense against a fungal pathogen, Candida albicans. We report in this study that Gsr-deficient mice exhibited substantially enhanced susceptibility to C. albicans challenge. Upon C. albicans infection, Gsr null mice exhibited dramatically increased fungal burdens in the kidneys, cytokine and chemokine storm, striking neutrophil infiltration and histological abnormalities in both the kidneys and hearts, and substantially elevated mortality. Large fungal foci surrounded by massive numbers of neutrophils were detected outside of glomerulus in the kidneys of Gsr null mice but not in wildtype mice. Examination of the bactericidal functions of the neutrophils from Gsr-deficient mice in vitro revealed normal phagocytosis and yet attenuated oxidative burst activity. Thus, Gsr-mediated redox regulation is crucial for fungal clearance during host defense against fungal challenge.