Candida Albicans FRE8 Encodes a Member of the NADPH Oxidase Family that Produces a Burst of ROS Important for Morphogenesis

Abstract

NADPH oxidase (NOX) enzymes, which produce reactive oxygen species (ROS), were until recently thought to occur only in multicellular organisms. ROS have important physiological effects such as acting as signaling molecules in biological processes or as defense mechanisms against invading microbes through oxidative damage. In this work, we demonstrate that the unicellular fungus Candida albicans is capable of producing an extracellular ROS burst using a member of the NOX enzyme family identified as Fre8. C. albicans is an opportunistic human fungal pathogen which undergoes morphologic transition between yeast, pseudohyphal, and hyphal forms. During morphogenesis, FRE8 is induced to produce ROS specifically at the growing tip of the polarized cell. The extracellular superoxide dismutase, Sod5, is also induced during morphogenesis and our findings are consistent with a model in which Sod5 acts as a partner for Fre8, converting Fre8-derived superoxide to the diffusible hydrogen peroxide molecule. Fre8∆/∆ mutants exhibit a morphogenesis defect in vitro and are specifically impaired in the development or maintenance of elongated hyphae in high density cultures. A fre8∆/∆ defect in hyphal formation was similarly observed in a disseminated candidiasis model. Moreover, in a rat catheter model, C. albicans fre8∆/∆ mutants showed deficiencies in biofilm formation. Together these studies demonstrate that like multicellular organisms, the unicellular C. albicans expresses NOX to produce ROS and this signal helps drive fungal morphogenesis in the animal host.