Abstract
Macrophages and neutrophils generate a potent burst of reactive oxygen and nitrogen species as a key aspect of the antimicrobial response. While most successful pathogens, including the fungus Candida albicans, encode enzymes for the detoxification of these compounds and repair of the resulting cellular damage, some species actively modulate immune function to suppress the generation of these toxic compounds. We report here that C. albicans actively inhibits macrophage production of nitric oxide (NO). NO production was blocked in a dose-dependent manner when live C. albicans were incubated with either cultured or bone marrow-derived mouse macrophages. While filamentous growth is a key virulence trait, yeast-locked fungal cells were still capable of dose-dependent NO suppression. C. albicans suppresses NO production from macrophages stimulated by exposure to IFN-γ and LPS or cells of the non-pathogenic Saccharomyces cerevisiae. The NO inhibitory activity was produced only when the fungal cells were in direct contact with macrophages, but the compound itself was secreted into the culture media. LPS/IFNγ stimulated macrophages cultured in cell-free conditioned media from co-cultures showed reduced levels of iNOS enzymatic activity and lower amounts of iNOS protein. Initial biochemical characterization of this activity indicates that the inhibitor is a small, aqueous, heat-stable compound. In summary, C. albicans actively blocks NO production by macrophages via a secreted mediator; these findings expand our understanding of phagocyte modulation by this important fungal pathogen and represent a potential target for intervention to enhance antifungal immune responses.
Highlights
Candida albicans is a commensal fungus residing on the skin and in the oral cavity, gastrointestinal tract, and vagina of the human host
To assess whether C. albicans affects nitric oxide (NO) production, RAW264.7 mouse macrophages were stimulated with lipopolysaccharide (LPS) and interferon-c (IFNc) to upregulate iNOS [24] and co-cultured with increasing amounts of C. albicans strain SC5314 for 24 hours
This phenomenon is quite robust as a ratio of one C. albicans cell per 100 macrophages (0.01:1) resulted in a,75% reduction in NO production, and an almost complete block was observed at fungal cell:macrophage ratios of 0.1:1
Summary
Candida albicans is a commensal fungus residing on the skin and in the oral cavity, gastrointestinal tract, and vagina of the human host. C. albicans cause a variety of superficial infections in individuals with certain risk factors, including oral thrush, vulvovaginal candidiasis, and various cutaneous infections. People with a significant immunodeficiency are more vulnerable to disseminated infection, which causes severe disease frequently resulting in death. The various defenses of the human innate immune system are primarily responsible for prevention of disseminated candidiasis [1]. Phagocytic cells such as macrophages and neutrophils are important mediators of innate immunity, initiating a robust antimicrobial response upon recognition and internalization of potential pathogens. Activation of macrophages and neutrophils results in the synthesis of antimicrobial effectors, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), the latter generated by the inducible nitric oxide synthase (iNOS, NOS2). Other studies have shown that NO production may not be required to prevent Candida infections [3,4,5], and the exact role of NO in antifungal defense remains unresolved
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