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

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.

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

“…Although most eukaryotes express only two or three SODs, C. albicans has six (26,(31)(32)(33). C. albicans Sod4, Sod5, and Sod6 are extracellular members of the Cu/Zn SOD family (33)(34)(35)(36). These SODs are highly irregular in that they are Cu-only (no Zn) as has been reported for M. tuberculosis SodC (37), and moreover exhibit a unique open active site that functions without an electrostatic loop for substrate guidance (24).…”

Candida albicansdimorphism as a therapeutic target

“…While neutrophils strongly inhibit growth (including the yeast-tohyphal transition) of C. albicans and can efficiently kill the fungus [19,45,46], yeast cells phagocytosed by macrophages may survive and produce hyphae, which pierce through the host membrane, rapidly killing the phagocyte and allowing C. albicans to escape [19,47]. The higher expression level of SOD5 (encoding an extracellular superoxide dismutase) in hyphae may counteract the oxidative burst of phagocytic cells and thus may help to survive attack of monocytes, macrophages and neutrophils [19,48,49]. Therefore, the hyphal transition is a critical event for escaping phagocytes.…”

Superoxide dismutases and glutaredoxins have a distinct role in the response of Candida albicans to oxidative stress generated by the chemical compounds menadione and diamide

“…However, while sod1Δ is hypersensitive to killing by a macrophage cell line in vitro (Hwang et al 2002), the same was not observed for sod5Δ (Martchenko et al 2004), indicating that the virulence role of Sod5 may be due to a resistance to different phagocytic cells. Frohner et al (2009) recently demonstrated that the Sod4 and Sod5 produced by innate immune response cells are extremely important as ROS scavengers. When both the SOD4 and SOD5 genes were disrupted in C. albicans, the double mutant generated (Δsod4/sod5) was extremely susceptible to in vitro macrophage killing (Frohner et al 2009).…”

“…Frohner et al (2009) recently demonstrated that the Sod4 and Sod5 produced by innate immune response cells are extremely important as ROS scavengers. When both the SOD4 and SOD5 genes were disrupted in C. albicans, the double mutant generated (Δsod4/sod5) was extremely susceptible to in vitro macrophage killing (Frohner et al 2009). …”

“…These enzymes possess antioxidant properties that catalyse the dismutation of O 2 -into molecular oxygen and H 2 O 2 , which can then be detoxified by Cat (Chaves et al 2007), thereby scavenging the toxic effects of O 2 (Frohner et al 2009). These Sods include cytoplasmic Sod1 and Sod3, mitochondrial Sod2 and the cell surface GP-anchored Sod4, Sod5 and Sod6 (Martchenko et al 2004, Frohner et al 2009, Bink et al 2011.…”