A Molecular Characterisation of the Fungal Zincophore System

Abstract

As both a commensal and a pathogen of humans, C. albicans colonises diverse anatomical sites, each of which can vary in its concentrations of essential trace metals, such as zinc. Moreover, as part of the immune system, these metals can be weaponised against pathogens; they may be sequestered from pathogens, or employed at high concentrations that render them antimicrobial. This is termed ‘nutritional immunity’ and C. albicans’ ability to successfully survive and colonise diverse micro-niches indicates the development of effective mechanisms to scavenge transition metals (i.e. iron, zinc, manganese and copper) from these micro-environments. The C. albicans Pra1-Zrt1 zincophore system is a zinc scavenging system unique to the fungal kingdom and it is the focus of this work. Orthologous components of zincophore systems were shown to have evolved dynamically throughout the evolutionary history of fungal phyla. Zinc bioavailability and pH of microenvironments have a significant impact on CaPra1 protein expression and C. albicans growth. Indeed, the combination of neutral pH and low zinc resulted in a secretome consisting of 75% of Pra1. The ability of C. albicans to raise extracellular pH by catabolising exogenous amino acids was shown to amplify Pra1 expression and activity. Importantly, the N-terminal extracellular domain of Zrt1 and the histidine/cysteine-rich C-terminus of Pra1 were shown to play important role for functionality of Zincophore system and pathogenicity of C. albicans. The dynamic change of the C. albicans secretome is an efficient means of adaptation to external stresses and host defences. This study also shows, for the first time, a critical role for the zincophore system in fungal virulence.