Nitrosative stress and combinatorial stresses in the pathogen Candida albicans

Abstract

Candida albicans is a major fungal pathogen that causes frequent mucosal infections in otherwise healthy individuals, and life-threatening systemic infections in immune-compromised patients. The first line of defence against Candida albicans is the release of reactive nitrogen species (RNS), reactive oxygen species (ROS) and cationic fluxes by macrophages and neutrophils. As a result robust responses to RNS, ROS and cationic stresses play major roles in the virulence of C. albicans . This fungus is exposed to all of these stresses simultaneously following phagocytosis. Consequently in this study we examined the responses of this pathogen to combinations of nitrosative, oxidative and cationic stress. The roles of the Cta4-Yhb1, Cap1, Hog1 and Mkc1 signalling pathways, which activate responses to individual nitrosative, oxidative, cationic and cell wall stresses, respectively, were examined. The sensitivity of null mutants to individual and combinatorial stresses was examined, and the activation of these pathways was confirmed by assaying the phosphorylation levels of the key protein kinases. Further evidence of the pathway activation was provided by transcription factor localisation and the expression of downstream target genes. We show that combinatorial nitrosative, oxidative and/or cationic stresses exert unexpected effects upon the classical stress signalling pathways. The relevance to C. albicans infections will be discussed.