The Fungal Pathogen Candida glabrata Does Not Depend on Surface Ferric Reductases for Iron Acquisition

Franziska Gerwien,Abu Safyan,Sascha Brunke,Bernhard Hube,Lydia Kasper,Stephanie Wisgott

doi:10.3389/fmicb.2017.01055

Abstract

Iron acquisition is a crucial virulence determinant for many bacteria and fungi, including the opportunistic fungal pathogens Candida albicans and C. glabrata. While the diverse strategies used by C. albicans for obtaining iron from the host are well-described, much less is known about the acquisition of this micronutrient from host sources by C. glabrata – a distant relative of C. albicans with closer evolutionary ties to Saccharomyces cerevisiae, which nonetheless causes severe clinical symptoms in humans. Here we show that C. glabrata is much more restricted than C. albicans in using host iron sources, lacking, for example, the ability to grow on transferrin and hemin/hemoglobin. Instead, C. glabrata is able to use ferritin and non-protein-bound iron (FeCl3) as iron sources in a pH-dependent manner. As in other fungal pathogens, iron-dependent growth requires the reductive high affinity (HA) iron uptake system. Typically highly conserved, this uptake mechanism normally relies on initial ferric reduction by cell-surface ferric reductases. The C. glabrata genome contains only three such putative ferric reductases, which were found to be dispensable for iron-dependent growth. In addition and in contrast to C. albicans and S. cerevisiae, we also detected no surface ferric reductase activity in C. glabrata. Instead, extracellular ferric reduction was found in this and the two other fungal species, which was largely dependent on an excreted low-molecular weight, non-protein ferric reductant. We therefore propose an iron acquisition strategy of C. glabrata which differs from other pathogenic fungi, such as C. albicans, in that it depends on a limited set of host iron sources and that it lacks the need for surface ferric reductases. Extracellular ferric reduction by a secreted molecule possibly compensates for the loss of surface ferric reductase activity in the HA iron uptake system.

Highlights

Iron is an essential micronutrient for almost all living organisms (Posey and Gherardini, 2000; Troxell et al, 2012), as it is indispensable for numerous cellular processes such as respiration, synthesis of iron-sulfur-clusters (Fe-S clusters), the tricarboxylic acid (TCA) cycle, and the synthesis of DNA, amino acids, lipids, and sterols (Schaible and Kaufmann, 2004)
To find common key components of iron acquisition and trafficking in C. glabrata, S. cerevisiae, and C. albicans, we searched their genome databases (Candida Genome Database, CGD, and Saccharomyces Genome Database, SGD) for orthologs with known or postulated ironrelated functions based on previously published data or ironrelated mutant phenotypes (Table 1 and Supplementary Table 1)
Our experiments confirmed again that C. albicans is able to use a broad spectrum of host iron sources including ferritin (Almeida et al, 2008), transferrin (Knight et al, 2005), hemin (Santos et al, 2003), and hemoglobin (Kuznets et al, 2014)

Summary

Introduction

Iron is an essential micronutrient for almost all living organisms (Posey and Gherardini, 2000; Troxell et al, 2012), as it is indispensable for numerous cellular processes such as respiration, synthesis of iron-sulfur-clusters (Fe-S clusters), the tricarboxylic acid (TCA) cycle, and the synthesis of DNA, amino acids, lipids, and sterols (Schaible and Kaufmann, 2004). Ferric Reduction in Candida glabrata is highly abundant in the environment, its bioavailability is low due to the low solubility of its most common form, ferric iron (Fe3+), under aerobic conditions (Haas et al, 2008). Iron acquisition is especially demanding, since they are dependent on the host’s iron supply. Host iron is typically bound to carrier proteins such as hemoglobin, the transport compound transferrin, or the storage molecule ferritin (Ratledge, 2007). Iron is actively withheld from infection sites to restrict the proliferation of invading pathogens. This host strategy is known as nutritional immunity (Hood and Skaar, 2012)

Objectives

Methods

Results

Conclusion