A systematic analysis reveals an essential role for high-affinity iron uptake system, hemolysin and CFEM domain-containing protein in iron homeostasis and virulence in Candida glabrata.

The Biochemical journal

PubMedID: 24987864

Srivastava VK, Suneetha KJ, Kaur R. A systematic analysis reveals an essential role for high-affinity iron uptake system, hemolysin and CFEM domain-containing protein in iron homeostasis and virulence in Candida glabrata. Biochem J. 2014;.
Iron is an essential nutrient for all living organisms and human pathogens employ a battery of factors to scavenge iron from the high-affinity iron-binding host proteins. Here, we have elucidated, via a candidate gene approach, major iron acquisition and homeostatic mechanisms operational in an opportunistic human fungal pathogen Candida glabrata. Phenotypic, biochemical and molecular analysis of a set of 13 C. glabrata strains deleted for proteins, potentially implicated in iron metabolism, revealed that the high-affinity reductive iron uptake system is required for utilization of alternate carbon sources and for growth under both in vitro iron-limiting and in vivo conditions. Further, we show for the first time that the cysteine-rich CFEM domain-containing cell wall structural protein, CgCcw14, and the putative hemolysin, CgMam3, are essential for maintenance of intracellular iron content, adherence to epithelial cells and virulence. Consistent with their roles in iron homeostasis, mitochondrial aconitase activity was lower and higher in mutants disrupted for high-affinity iron transport, and hemolysin, respectively. Additionally, we present evidence that the mitochondrial frataxin, CgYfh1, is pivotal to iron metabolism. Besides yielding insights into major in vitro and in vivo iron acquisition strategies, our findings establish high-affinity iron uptake mechanisms as critical virulence determinants in C. glabrata.