Ferric Reduction Is a Potential Iron Acquisition Mechanism forHistoplasma capsulatum

Abstract

For the fungus Histoplasma capsulatum, and for other microbial pathogens, iron is an essential nutrient. Iron sequestration in response to infection is a demonstrated host defense mechanism; thus, iron acquisition may be considered an important pathogenic determinant. H. capsulatum is known to secrete Fe(III)-binding hydroxamate siderophores, which is one common microbial process for acquiring iron. Here, we report H. capsulatumferric reduction activities in whole yeast cells and in both high- and low-molecular-weight fractions of culture supernatants. Each of these activities was induced or derepressed by growth under iron-limiting conditions, a phenomenon often associated with specific iron acquisition mechanisms. The high-molecular-weight culture supernatant activity was enhanced by the addition of reduced glutathione, was proteinase K sensitive and heat labile, and could utilize ferric chloride, ferric citrate, and human holotransferrin as substrates. The low-molecular-weight culture supernatant activity was resistant to proteinase K digestion. These results are consistent with the expression by H. capsulatum of both enzymatic ferric reductase and nonproteinaceous ferric reductant, both of which are regulated by iron availability. Such components could be involved in fungal acquisition of iron from inorganic or organic ferric salts, fromH. capsulatum hydroxamate siderophores, or from host Fe(III)-binding proteins, such as transferrin.

Differentially regulated high‐affinity iron assimilation systems support growth of the various cell types in the dimorphic pathogen Talaromyces marneffei

“…The second iron uptake system involves the secretion of siderophores, low molecular mass ferric iron-specific chelators, to mobilize and transport iron (Timmerman and Woods, 1999;Schrettl et al, 2004). Siderophore chelated ferric iron is recovered by cells either by specific high-affinity siderophore transporters that take up the entire siderophore-iron complex or through delivery to the RIA system (Ardon et al, 2001;Yun et al, 2001).…”

Endosomal vacuoles of the prepupal salivary glands of Drosophila play an essential role in the metabolic reallocation of iron

“…While we were unable to detect iron directly using Prussian blue, we found that the redox-active and thiol-sensitive fluorescent probe, CellTracker Blue CMAC, which is known to measure reduced glutathione (GSH), shows a progressive increase in level inside the large mature vacuoles. This indicates that these large vacuoles/endosomes accumulate increased amounts of GSH (Fricker & Meyer, 2001;Tauskela et al, 2000;Timmerman & Woods, 1999). Indeed, the increased accumulation of GSH in vacuoles can be prevented by pretreating the incubation medium or feeding third instar larvae with deferoxamine, deferiprone, or rhodotorulic acid, three different iron chelators.…”

The Histoplasma capsulatum vacuolar ATPase is required for iron homeostasis, intracellular replication in macrophages and virulence in a murine model of histoplasmosis

“…Histoplasma capsulatum yeasts secrete hydroxamate siderophores under iron-limited conditions (Howard et al, 2000), and H. capsulatum yeasts are able to chelate iron from holotransferrin (Timmerman and Woods, 1999). Therefore, we hypothesized that WT yeasts might secrete siderophores to complement the growth of vma1::HPH mutants.…”