Abstract
Mammalian innate immune cells produce reactive oxygen species (ROS) in the oxidative burst reaction to destroy invading microbial pathogens. Using quantitative real-time ROS assays, we show here that both yeast and filamentous forms of the opportunistic human fungal pathogen Candida albicans trigger ROS production in primary innate immune cells such as macrophages and dendritic cells. Through a reverse genetic approach, we demonstrate that coculture of macrophages or myeloid dendritic cells with C. albicans cells lacking the superoxide dismutase (SOD) Sod5 leads to massive extracellular ROS accumulation in vitro. ROS accumulation was further increased in coculture with fungal cells devoid of both Sod4 and Sod5. Survival experiments show that C. albicans mutants lacking Sod5 and Sod4 exhibit a severe loss of viability in the presence of macrophages in vitro. The reduced viability of sod5Δ/Δ and sod4Δ/Δsod5Δ/Δ mutants relative to wild type is not evident with macrophages from gp91phox−/− mice defective in the oxidative burst activity, demonstrating a ROS-dependent killing activity of macrophages targeting fungal pathogens. These data show a physiological role for cell surface SODs in detoxifying ROS, and suggest a mechanism whereby C. albicans, and perhaps many other microbial pathogens, can evade host immune surveillance in vivo.
Highlights
Invasive Candida albicans infections are life-threatening clinical conditions affecting immunosuppressed patients and those with general defects in the immune system
Using quantitative real-time reactive oxygen species (ROS) assays, we show here that both yeast and filamentous forms of the opportunistic human fungal pathogen Candida albicans trigger ROS production in primary innate immune cells such as macrophages and dendritic cells
Through a reverse genetic approach, we demonstrate that coculture of macrophages or myeloid dendritic cells with C. albicans cells lacking the superoxide dismutase (SOD) Sod5 leads to massive extracellular ROS accumulation in vitro
Summary
Invasive Candida albicans infections are life-threatening clinical conditions affecting immunosuppressed patients and those with general defects in the immune system. The earliest host response to fungal pathogens, including C. albicans, relies on fungal recognition by innate immune cells such as dendritic cells, macrophages and neutrophils and involves pattern recognition receptors, followed by the subsequent phagocytosis and elimination of microbial pathogens (Brown and Gordon, 2005; Akira et al, 2006; Jouault et al, 2006; Taylor, 2007; Gow et al, 2007). ROS production is initiated through assembly and activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes (Babior, 2004). This triggers the respiratory burst by generating superoxide anions (O2-) (Schrenzel et al, 1998), which are subsequently converted to hydrogen peroxide (H2O2), hydroxyl radical (OH°) and hypochlorous acid, the latter conversion only taking place in neutrophils
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