Chen C, Pande K, French SD, Tuch BB, Noble SM.. An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis. Cell Host Microbe 10: 118-135

Department of Medicine, Division of Infectious Diseases, University of California San Francisco, USA.
Cell host & microbe (Impact Factor: 12.33). 08/2011; 10(2):118-35. DOI: 10.1016/j.chom.2011.07.005
Source: PubMed


The mammalian gastrointestinal tract and bloodstream are highly disparate biological niches that differ in concentrations of nutrients such as iron. However, some commensal-pathogenic microorganisms, such as the yeast Candida albicans, thrive in both environments. We report the evolution of a transcription circuit in C. albicans that controls iron uptake and determines its fitness in both niches. Our analysis of DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved iron-responsive transcriptional repressors, Sfu1 and Hap43. Sef1 activates iron-uptake genes and promotes virulence in a mouse model of bloodstream infection, whereas Sfu1 represses iron-uptake genes and is dispensable for virulence but promotes gastrointestinal commensalism. Thus, C. albicans can alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut, and this may represent a fundamental attribute of gastrointestinal commensal-pathogens.

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    • "In contrast, Sef1, a transcriptional activator of both iron uptake 685 and iron-utilization genes (amongst other targets), was necessary for virulence in bloodstream infections in which iron was poorly available due to its sequestration by the host. Nevertheless , relative to the WT strain, mutants lacking either SEF1 or SFU1 were impaired in their ability to persist in the murine gut 690 over a 15-day period (Chen et al. 2011). Interestingly, the GUT cells described by Pande, Chen and Noble (2013) were also found to downregulate expression of iron-acquisition genes, which is consistent with their apparent optimization for GI colonization. "
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    ABSTRACT: Candida albicans is a polymorphic yeast species that often forms part of the commensal gastrointestinal mycobiota of healthy humans. It is also an important opportunistic pathogen. A tripartite interaction involving Candida albicans, the resident microbiota and host immunity maintains C. albicans in its commensal form. The influence of each of these factors on C. albicans carriage is considered herein, with particular focus on the mycobiota and the approaches used to study it, models of gastrointestinal colonisation by C. albicans, the C. albicans genes and phenotypes that are necessary for commensalism and the host factors that influence C. albicans carriage.
    FEMS Yeast Research 09/2015; DOI:10.1093/femsyr/fov081 · 2.82 Impact Factor
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    • "Unlike the other CFEM-containing proteins, which are attached to both the cell wall and the plasma membrane, the small, secretory protein Csa2 does not possess a glycosylphosphatidylinositol anchor (Sosinska et al., 2008; Weissman et al., 2008; Sorgo et al., 2010, 2011). Transcriptional studies have indicated that several cell wall proteins are regulated by iron availability and that the increased expression of CFEM-containing proteins in conditions of iron starvation supports their involvement in iron acquisition (Lan et al., 2004; Chen et al., 2011). The precise roles of these heme-binding proteins in virulence have not yet been well described; in particular, little is known about the function of Csa2 in heme-iron uptake. "
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    ABSTRACT: Csa2 is a member of both the Candida albicans Rbt5 protein family and the CFEM (Common in Fungal Extracellular Membranes) protein superfamily. CFEM proteins are characterized by an internal domain containing eight equally spaced cysteine residues. Csa2 is involved in iron uptake from hemoglobin and heme proteins; however, its precise role is unclear. Here, we provide quantitative evidence of the involvement of Csa2 in the utilization of iron from human hemoglobin during C. albicans hyphal growth. The ability of the hyphal form of the wild-type, a homozygote csa2Δ mutant, and a complemented strain of C. albicans to utilize hemoglobin as an iron source under iron-restricted conditions was examined through growth studies and a crystal violet-staining assay. Hemoglobin-binding activity was assessed indirectly by using a hemoglobin-sensitized tube method. Although hyphal growth of the wild-type and csa2Δ/Δ::CSA2 strains was completely recovered when a high concentration of human hemoglobin was added to the iron-restricted culture medium, the recovery of the csa2Δ/Δ mutant was significantly diminished. Furthermore, hemoglobin binding was impaired in the csa2Δ/Δ mutant compared with the wild-type and csa2Δ/Δ::CSA2 strains, revealing that Csa2 is involved in the utilization of hemoglobin as an iron source by the hyphal form of C. albicans.This article is protected by copyright. All rights reserved.
    FEMS Yeast Research 05/2014; 14(4). DOI:10.1111/1567-1364.12160 · 2.82 Impact Factor
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    • "The ability of iron acquisition is considered as a prerequisite in pathogen–host interactions and has a profound influence on pathogenicity and virulence [1] [2] [3]. The competition between pathogens and their hosts for iron impels the evolution of various strategies in C. albicans to tightly regulate iron acquisition, storage and utilization [4] [5]. Therefore, a deeper understanding of iron homeostasis in morphogenesis and pathogenicity will provide a novel insight into the treatment of C. albicans infection and drug development. "
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    ABSTRACT: Iron bioavailability is crucial for mitochondrial metabolism and biosynthesis. Dysregulation of cellular iron homeostasis affects multiple aspects of mitochondrial physiology and cellular processes. However, the intracellular iron trafficking pathway in C. albicans remains unclear. In this study, we characterized the Mrs4-Ccc1-Smf3 pathway, and demonstrated its important role in maintaining cellular iron levels. Double deletion of vacuolar iron exporter SMF3 and mitochondrial iron transporter MRS4 further elevated cellular iron levels in comparison with the single MRS4 deletion. However, deletion of vacuolar iron importer CCC1 in the mrs4∆/∆ mutant restored cellular iron homeostasis to normal wild-type levels, and also normalized most of the defective phenotypes in response to various environmental stresses. Our results also suggested that both Mrs4 and Ccc1 contributed to the maintenance of mitochondrial function. The mrs4∆/∆ and mrs4∆/∆smf3∆/∆ mutants exhibited an obvious decrease in aconitase activities and mitochondrial membrane potential, whereas deletion of CCC1 in the mrs4∆/∆ mutant effectively rescued these defects. Furthermore, we also found that the Mrs4-Ccc1-Smf3 pathway was indispensable for cell-wall stability, antifungal drug tolerance, filamentous growth and virulence, supporting the novel viewpoint that mitochondria might be the promising target for better antifungal therapies. Interestingly, the addition of exogenous iron failed to rescue the defects on non-fermentable carbon sources or hyphae-inducing medium, indicating that the defects in mitochondrial respiration and filamentous development might result from the disturbance of cellular iron homeostasis rather than environmental iron deprivation. Taken together, our results propose the Mrs4-Ccc1-Smf3 pathway as a potentially attractive target for antifungal drug development.
    Biochimica et Biophysica Acta 12/2013; 1843(3). DOI:10.1016/j.bbamcr.2013.12.009 · 4.66 Impact Factor
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