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Recognition of Candida spp. by immune cells is mediated by dedicated pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and lectins expressed on innate immune cells (e.g., macrophages, neutrophils and dendritic cells (DCs)). PRRs recognize Candida-specific pathogen-associated molecular patterns (PAMPs). Binding of fungal PAMPs (e.g., cell wall sugar polymers and proteins, fungal nucleic acids) to PRRs triggers the activation of innate effector cells. Recent findings underscore the role of DCs in relaying PAMP information through their PRRs to stimulate the adaptive response. In agreement, deficiencies in certain PRRs strongly impair survival to Candida infections in mice and is associated with enhanced susceptibility to mucocutaneous fungal infections in humans. Understanding the complex signaling networks protecting the host against fungal pathogens remains a challenge in the field., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The incidence of invasive fungal diseases has increased over the past decades, particularly in relation with the increase of immunocompromised patient cohorts (e.g., HIV-infected patients, transplant recipients, immunosuppressed patients with cancer). Opportunistic fungal pathogens such as Candida spp. are most often associated with serious systemic infections. Currently available antifungal drugs are rather unspecific, often with severe side effects. In some cases, their prophylactic use has favored emergence of resistant fungal strains. Major antifungal drugs target the biosynthesis of lipid components of the fungal plasma membrane or the assembly of the cell wall. For a more specific and efficient treatment and prevention of fungal infection, new therapeutic strategies are needed, including strengthening or stimulation of the residual host immune response. Achieving such a goal requires a better understanding of factors important for the defense and the survival of the host combating Candida spp. Where possible, primary cultures of mammalian immune cells of the innate immune system constitute a better suited model than transformed cell lines to study host-pathogen response and virulence. Hence, in vitro primary cell culture systems are a good strategy for a first screening of mutant strains of Candida spp. to identify virulence traits with regard to host cell response and pathogen invasion.

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/Δ sod5Δ/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. [ABSTRACT FROM AUTHOR]