Expression Patterns in Reductive Iron Assimilation and Functional Consequences during Phagocytosis of , an Emerging Cause of Mucormycosis.

Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus , three, four and three copies were identified for , and genes, respectively. As in other fungi, and are syntenic and co-expressed in . Expression of , and genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in II and III, I and II, as well as I and II suggesting a functional role in pathogenesis. The syntenic I- I gene pair is co-expressed during germination, whereas II- II is co-expressed during hyphal proliferation. I, II and IV were overexpressed in to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for I, but possible functions of II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between and macrophages.