The Siderophore Iron Transporter ofCandida albicans(Sit1p/Arn1p) Mediates Uptake of Ferrichrome-Type Siderophores and Is Required for Epithelial Invasion

Abstract

The human fungal pathogen Candida albicans contains a close homologue of yeast siderophore transporters, designated Sit1p/Arn1p. We have characterized the function of SIT1 in C. albicans by constructing sit1 deletion strains and testing their virulence and ability to utilize a range of siderophores and other iron complexes. sit1 mutant strains are defective in the uptake of ferrichrome-type siderophores including ferricrocin, ferrichrysin, ferrirubin, coprogen, and triacetylfusarinine C. A mutation of FTR1 did not impair the use of these siderophores but did affect the uptake of ferrioxamines E and B, as well as of ferric citrate, indicating that their utilization was independent of Sit1p. Hemin was a source of iron for both sit1 and ftr1 mutants, suggesting a pathway of hemin uptake distinct from that of siderophores and iron salts. Heterologous expression of SIT1 in the yeast Saccharomyces cerevisiae confirmed the function of Sit1p as a transporter for ferrichrome-type siderophores. The sit1 mutant was defective in infection of a reconstituted human epithelium as a model for human oral mucosa, while the SIT1 strain was invasive. In contrast, both sit1 and SIT1 strains were equally virulent in the mouse model of systemic infection. These results suggest that siderophore uptake by Sit1p/ Arn1p is required in a specific process of C. albicans infection, namely epithelial invasion and penetration, while in the blood or within organs other sources of iron, including heme, may be used.

Desketoneoenactin-Siderophore Conjugates for Candida : Evidence of Iron Transport-Dependent Species Selectivity

“…Hemin, used as an independent control, could also restore the growth of the ⌬ftr1⌬ftr2 mutant strain, as it did with the ⌬sit1/arn1 mutant strain. This result is consistent with previous studies that suggested a distinct uptake pathway for hemin (5,18). Susceptibility of Candida albicans ⌬sit1/arn1 mutant strain to siderophore-drug conjugates.…”

“…We can speculate that the ability of conjugates to perform well in an iron-deficient environment similar to that found at the mucosal surface of the mammalian host (17) and the ability of the conjugates to associate with Candida cells through high-affinity iron-transport receptors may represent valuable properties of antimicrobial molecules during therapy. This is supported by the results of Heymann et al (5) showing that the ferrichrome receptor CaSit1/CaArn1 was required for epithelial invasion and by the finding that high-affinity transport systems have been shown to transport specific substrates more efficiently into cells than simple diffusion when the concentration of the substrate outside the microbial cells is low (12), a situation that may occur between doses of antibiotics in a therapeutic regimen.…”

“…The production of siderophores of the hydroxamate type by C. albicans has also been reported, but their structures are still unknown (7,16). C. albicans can utilize siderophores that are produced by other microorganisms, and a transporter that mediates the uptake of ferrichrome-type siderophores encoded by the genes Caarn1/ Casit1 has been described (1,5,6). The expression of both reductive and nonreductive uptake systems is regulated by iron availability.…”

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

“…We also included an additional 15 ironrelated genes that showed Cap2-dependent up-regulation (six genes) or down-regulation (nine genes), for which the L_H_Fe data were not available. Interestingly, eight of the 18 up-regulated genes in the CAP2/cap2⌬ data have been shown experimentally to be involved in iron uptake pathways, viz., SIT1 encoding siderophore transporter (72) , FET3, FTR1, FRP1, CFL5, and FRE9 encoding reductive iron uptake (73,74), and RBT5 and HMX1 being part of heme uptake (35,75,76) pathways (Fig. 4C).…”

Identificação funcional e estrutura genômica de genes nucleares associados à atividade da citocromo C oxidase de Paracoccidioides brasiliensis.

“…Este fato é corroborado pelos relatos de que o transporte de sideróferos é requerido no processo especifico de infecção, denominado "invasão epitelial e penetração por Cândida albicans" (Heymann et al, 2002;Hu et al, 2002). Considerando que as vias biosintéticas de sideróferos são ausentes em células humanas, as vias de biosíntese de sideróferos em organismos patogênicos representam fortes candidatos a alvos de agentes quimioterápicos (Eisendle et al, 2003).…”