Pathogenic Yeasts Deploy Cell Surface Receptors to Acquire Iron in Vertebrate Hosts

Brown et al. (2012) [1] recently highlighted the growing threat that fungal pathogens pose for humans, as well as the pressing need for additional antifungal drugs and efficacious vaccines. In this context, the process of iron acquisition presents compelling opportunities to prevent or treat fungal diseases because iron is an essential nutrient for pathogen proliferation in vertebrate hosts. Fungi and other pathogens must deploy competitive uptake mechanisms to steal iron from host sources and overcome the iron sequestration associated with nutritional immunity [2]. These extracellular and surface uptake functions may provide readily accessible targets for drugs to block iron uptake, and iron transporters might also be exploited to introduce antifungal agents into fungal cells [3,4]. Additionally, extracellular or exposed transporters may be useful vaccine targets to block iron uptake and pathogen proliferation. Mechanisms of iron acquisition have been well characterized in many microbial pathogens, and information is rapidly accumulating for fungal pathogens [5–9]. Fungi generally acquire iron by several mechanisms including: 1) the production and uptake of siderophores; 2) the use of a ferroxidase-iron permease complex for high-affinity uptake; 3) the transport of ferrous iron; and 4) the acquisition of iron from heme and hemoglobin [7–9]. Reductases in the plasma membrane and secreted reductants facilitate the reduction of ferric iron to ferrous iron for highor low-affinity uptake [7–9]. The exploration of these mechanisms in fungal pathogens has revealed intriguing connections between cell surface molecules (cell wall and secreted proteins, capsular polysaccharide, and biofilms) and functions for iron acquisition from vertebrate sources (Figure 1A, B). Here we highlight these connections for the pathogenic yeasts Candida albicans and Cryptococcus neoformans. We also discuss the extent to which the newly identified functions add depth to our understanding of iron acquisition by fungi and illustrate the complex integration of iron sensing and virulence.