Differential susceptibility of mitogen-activated protein kinase pathway mutants to oxidative-mediated killing by phagocytes in the fungal pathogen Candida albicans

Abstract

The role of four mitogen-activated protein (MAP) kinase pathways in the survival of Candida albicans following infection of human phagocytes has been addressed through the analysis of mutants defective in their respective MAP kinase. While the contribution of the cell integrity (Mkc1-mediated) or mating (Cek2-mediated) pathways is relatively minor to survival, clear and opposite effects were observed for cek1 and hog1 mutants, despite the fact that these two MAP kinases are important virulence determinants in the mouse model of experimental infection. The Cek1-mediated pathway is involved in sensitivity to phagocyte-mediated killing, while the HOG pathway contributes to the survival of the fungal cells in this interaction. Furthermore, reporter genes have been developed to quantify oxidative and nitrosative stress. hog1 mutants show an oxidative and nitrosative stress response augmented - albeit non-protective - when challenged with oxidants and NO donors in vitro or phagocytic cells (macrophages, neutrophils and the myelomonocytic cell line HL-60), suggesting this as the cause of their reduced virulence in the murine model of infection. These data have important consequences for the development of novel antifungal therapies to combat against fungal infection.