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Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance.

Frohner IE, Bourgeois C, Yatsyk K, Majer O, Kuchler K - Mol. Microbiol. (2008)

Bottom Line: 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 sod5Delta/Delta and sod4Delta/Deltasod5Delta/Delta 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.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna, Christian Doppler Laboratory for Infection Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter; A-1030 Vienna, Austria.

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 sod5Delta/Delta and sod4Delta/Deltasod5Delta/Delta 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.

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Model for Sod4 and Sod5-mediated protection against respiratory burst. Upon contact with BMDMs and mDCs, Sod4 and Sod5 anchored at the C. albicans (C.a) surface (left) degrade superoxide anions (O2−) to hydrogen peroxide (H2O2). The lack of the Sod4 and Sod5 (right) causes ROS accumulation in the medium and perhaps inside the phagosomes (phago), which results in enhanced killing of C. albicans. Production of mitochondrial ROS (Mit) is unaffected.
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fig06: Model for Sod4 and Sod5-mediated protection against respiratory burst. Upon contact with BMDMs and mDCs, Sod4 and Sod5 anchored at the C. albicans (C.a) surface (left) degrade superoxide anions (O2−) to hydrogen peroxide (H2O2). The lack of the Sod4 and Sod5 (right) causes ROS accumulation in the medium and perhaps inside the phagosomes (phago), which results in enhanced killing of C. albicans. Production of mitochondrial ROS (Mit) is unaffected.

Mentions: Based on our results, we propose that C. albicans can escape host-generated oxidative burst (Fig. 6). Adhesion, recognition and phagocytosis of fungal cells by innate immune cells trigger an immediate and rapid assembly of the ROS machinery at the cell surface or in the forming phagosomal membrane, preceding phagocytosis and persisting throughout phagosomal formation (Nauseef, 2004). Concomitantly, host temperature and adhesion may enhance SOD4 and SOD5 expression, followed by the elimination of extracellular and perhaps phagosomal ROS produced by host cells. In our in vitro assay during phagocytosis, substrate and enzyme may become trapped in the phagosomes. Hence, ROS production may also continue within the phagosomes. The SOD-mediated decay of host-derived ROS perhaps facilitates intraphagosomal survival of fungal cells, which would facilitate killing of the host cells. Taken together, these data reveal a physiological function of cell surface SODs in evading immune surveillance, thereby facilitating invasion and ultimately dissemination of fungal pathogens in the mammalian host (Fig. 6).


Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance.

Frohner IE, Bourgeois C, Yatsyk K, Majer O, Kuchler K - Mol. Microbiol. (2008)

Model for Sod4 and Sod5-mediated protection against respiratory burst. Upon contact with BMDMs and mDCs, Sod4 and Sod5 anchored at the C. albicans (C.a) surface (left) degrade superoxide anions (O2−) to hydrogen peroxide (H2O2). The lack of the Sod4 and Sod5 (right) causes ROS accumulation in the medium and perhaps inside the phagosomes (phago), which results in enhanced killing of C. albicans. Production of mitochondrial ROS (Mit) is unaffected.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713856&req=5

fig06: Model for Sod4 and Sod5-mediated protection against respiratory burst. Upon contact with BMDMs and mDCs, Sod4 and Sod5 anchored at the C. albicans (C.a) surface (left) degrade superoxide anions (O2−) to hydrogen peroxide (H2O2). The lack of the Sod4 and Sod5 (right) causes ROS accumulation in the medium and perhaps inside the phagosomes (phago), which results in enhanced killing of C. albicans. Production of mitochondrial ROS (Mit) is unaffected.
Mentions: Based on our results, we propose that C. albicans can escape host-generated oxidative burst (Fig. 6). Adhesion, recognition and phagocytosis of fungal cells by innate immune cells trigger an immediate and rapid assembly of the ROS machinery at the cell surface or in the forming phagosomal membrane, preceding phagocytosis and persisting throughout phagosomal formation (Nauseef, 2004). Concomitantly, host temperature and adhesion may enhance SOD4 and SOD5 expression, followed by the elimination of extracellular and perhaps phagosomal ROS produced by host cells. In our in vitro assay during phagocytosis, substrate and enzyme may become trapped in the phagosomes. Hence, ROS production may also continue within the phagosomes. The SOD-mediated decay of host-derived ROS perhaps facilitates intraphagosomal survival of fungal cells, which would facilitate killing of the host cells. Taken together, these data reveal a physiological function of cell surface SODs in evading immune surveillance, thereby facilitating invasion and ultimately dissemination of fungal pathogens in the mammalian host (Fig. 6).

Bottom Line: 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 sod5Delta/Delta and sod4Delta/Deltasod5Delta/Delta 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.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna, Christian Doppler Laboratory for Infection Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter; A-1030 Vienna, Austria.

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 sod5Delta/Delta and sod4Delta/Deltasod5Delta/Delta 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.

Show MeSH