Iron at the Centre of Candida albicans Interactions (original) (raw)
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Regulatory Networks Affected by Iron Availability In Candida Albicans
Molecular …, 2004
Iron, an essential element for almost every organism, serves as a regulatory signal for the expression of virulence determinants in many prokaryotic and eukaryotic pathogens. Using a custom Affymetrix GeneChip © representing the entire Candida albicans genome, we examined the changes in genome-wide gene expression in this opportunistic pathogen as a function of alterations in environmental concentrations of iron. A total of 526 open reading frame (ORF) transcripts are more highly expressed when the levels of available iron are low, while 626 ORF transcripts are more highly expressed in high-iron conditions. The transcripts dominantly affected by iron concentration range from those associated with cell-surface properties to others which affect mitochondrial function, iron transport and virulence-related secreted hydrolases. Moreover gene expression as assayed in DNA microarrays confirms and extends reports of alterations in cell-surface antigens and drug sensitivity correlated with iron availability. To understand how these genes and pathways might be regulated, we isolated a gene designated SFU1 that encodes a homologue of the Ustilago maydis URBS1, a transcriptional repressor of siderophore uptake/ biosynthesis. Comparisons between wild-type and SFU1-null mutant strains revealed 139 potential target genes of Sfu1p; many of which are iron-responsive. Together, these results not only expand our understanding of global iron regulation in C. albicans , but also provide insights into the potential role of iron availability in C. albicans virulence.
Iron restriction-induced adaptations in the wall proteome of Candida albicans
Microbiology, 2013
The opportunistic fungal pathogen Candida albicans has developed various ways to overcome iron restriction in a mammalian host. Using different surface proteins, among them membrane-and wall-localized GPI-proteins, it can exploit iron from host hemoglobin, ferritin, and transferrin. Culturing C. albicans in rich medium supplemented with the ferrous iron chelator bathophenanthroline disulfonic acid or in the minimal medium yeast nitrogen base resulted in a strong decrease of the iron content of the cells. Mass spectrometric analysis of the changes in the wall proteome of C. albicans upon iron restriction showed a strong increase in the levels of the GPI-modified adhesin Als3, which also serves as a ferritin receptor, and of the GPI-modified, CFEM domain-containing proteins Csa1, Pga7, Pga10, and Rbt5. The wall levels of the GPI-modified proteins Hyr1, the adhesin Als4, and the copper-and zinc-containing superoxide dismutase Sod4 also strongly increased, whereas the levels of Tos1 (a non-GPI protein) and the GPI-modified adhesin Als2 strongly decreased. Strikingly, peptides derived from the CFEM domain of the heme-binding proteins Csa1, Pga10 and Rbt5 were capable of forming iron adduct ions during mass spectrometric analysis, consistent with a key role of this domain in heme binding.
Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans
Frontiers in cellular and infection microbiology, 2013
Iron is the most abundant transition metal in the human body and its bioavailability is stringently controlled. In particular, iron is tightly bound to host proteins such as transferrin to maintain homeostasis, to limit potential damage caused by iron toxicity under physiological conditions and to restrict access by pathogens. Therefore, iron acquisition during infection of a human host is a challenge that must be surmounted by every successful pathogenic microorganism. Iron is essential for bacterial and fungal physiological processes such as DNA replication, transcription, metabolism, and energy generation via respiration. Hence, pathogenic bacteria and fungi have developed sophisticated strategies to gain access to iron from host sources. Indeed, siderophore production and transport, iron acquisition from heme and host iron-containing proteins such as hemoglobin and transferrin, and reduction of ferric to ferrous iron with subsequent transport are all strategies found in bacteria...
2008
Iron sequestration by host iron-binding proteins is an important mechanism of resistance to microbial infections. Inside oral epithelial cells, iron is stored within ferritin, and is therefore not usually accessible to pathogenic microbes. We observed that the ferritin concentration within oral epithelial cells was directly related to their susceptibility to damage by the human pathogenic fungus, Candida albicans. Thus, we hypothesized that host ferritin is used as an iron source by this organism. We found that C. albicans was able to grow on agar at physiological pH with ferritin as the sole source of iron, while the baker's yeast Saccharomyces cerevisiae could not. A screen of C. albicans mutants lacking components of each of the three known iron acquisition systems revealed that only the reductive pathway is involved in iron utilization from ferritin by this fungus. Additionally, C. albicans hyphae, but not yeast cells, bound ferritin, and this binding was crucial for iron acquisition from ferritin. Transcriptional profiling of wild-type and hyphal-defective C. albicans strains suggested that the C. albicans invasin-like protein Als3 is required for ferritin binding. Hyphae of an Dals3 null mutant had a strongly reduced ability to bind ferritin and these mutant cells grew poorly on agar plates with ferritin as the sole source of iron. Heterologous expression of Als3, but not Als1 or Als5, two closely related members of the Als protein family, allowed S. cerevisiae to bind ferritin. Immunocytochemical localization of ferritin in epithelial cells infected with C. albicans showed ferritin surrounding invading hyphae of the wild-type, but not the Dals3 mutant strain. This mutant was also unable to damage epithelial cells in vitro. Therefore, C. albicans can exploit iron from ferritin via morphology dependent binding through Als3, suggesting that this single protein has multiple virulence attributes.
Iron and infection: competition between host and microbes for a precious element
Best Practice & Research Clinical Haematology, 2002
During infection microbes attack host tissues, causing damage to speci®c organs, sepsis or even death. For proliferation microbes desperately need iron for which they have to compete with the host. Micro-organisms have developed an abundant number of strategies to acquire iron from their speci®c environment and to transport the element to sites of incorporation into biologically important molecules. As part of the non-speci®c defence mechanisms against infection, the body modi®es iron metabolism in order to make iron less available for microorganisms. Such processes have a profound eect on the immune system and are also expressed in other forms of in¯ammation. Microbial iron transport systems are explored as targets for antibiotic treatment and vaccines. In particular, iron chelators, used for the treatment of iron overload may become important drugs for ®ghting bacterial and viral infections.
PLoS Pathogens, 2013
Nutritional immunity -the withholding of nutrients by the host -has long been recognised as an important factor that shapes bacterial-host interactions. However, the dynamics of nutrient availability within local host niches during fungal infection are poorly defined. We have combined laser ablation-inductively coupled plasma mass spectrometry (LA-ICP MS), MALDI imaging and immunohistochemistry with microtranscriptomics to examine iron homeostasis in the host and pathogen in the murine model of systemic candidiasis. Dramatic changes in the renal iron landscape occur during disease progression. The infection perturbs global iron homeostasis in the host leading to iron accumulation in the renal medulla. Paradoxically, this is accompanied by nutritional immunity in the renal cortex as iron exclusion zones emerge locally around fungal lesions. These exclusion zones correlate with immune infiltrates and haem oxygenase 1-expressing host cells. This local nutritional immunity decreases iron availability, leading to a switch in iron acquisition mechanisms within mature fungal lesions, as revealed by laser capture microdissection and qRT-PCR analyses. Therefore, a complex interplay of systemic and local events influences iron homeostasis and pathogen-host dynamics during disease progression. Citation: Potrykus J, Stead D, MacCallum DM, Urgast DS, Raab A, et al. (2013) Fungal Iron Availability during Deep Seated Candidiasis Is Defined by a Complex Interplay Involving Systemic and Local Events. PLoS Pathog 9(10): e1003676.
Endothelial Cell Injury Caused by Candida albicans Is Dependent on Iron
1998
Although it is known that Candida albicans causes endothelial cell injury, in vitro and in vivo, the mechanism by which this process occurs remains unknown. Iron is critical for the induction of injury in many types of host cells. Therefore, we investigated the role of iron in Candida-induced endothelial cell injury. We found that pretreatment of endothelial cells with the
NAR Genomics and Bioinformatics
Candida glabrata is a cause of life-threatening invasive infections especially in elderly and immunocompromised patients. Part of human digestive and urogenital microbiota, C. glabrata faces varying iron availability, low during infection or high in digestive and urogenital tracts. To maintain its homeostasis, C. glabrata must get enough iron for essential cellular processes and resist toxic iron excess. The response of this pathogen to both depletion and lethal excess of iron at 30°C have been described in the literature using different strains and iron sources. However, adaptation to iron variations at 37°C, the human body temperature and to gentle overload, is poorly known. In this study, we performed transcriptomic experiments at 30°C and 37°C with low and high but sub-lethal ferrous concentrations. We identified iron responsive genes and clarified the potential effect of temperature on iron homeostasis. Our exploration of the datasets was facilitated by the inference of functio...
Iron homeostasis in host and gut bacteria – a complex interrelationship
Gut Microbes
Iron deficiency is the most frequent nutritional deficiency in the world with an estimated 1.4 billion people affected. The usual way to fight iron deficiency is iron fortification, but this approach is not always effective and can have undesirable side effects including an increase in the growth and virulence of gut bacterial pathogens responsible for diarrhea and gut inflammation. Iron is mainly absorbed in the duodenum and is tightly regulated in mammals. Unabsorbed iron enters the colonic lumen where many microorganisms, referred to as gut microbiota, reside. Iron is essential for these bacteria, and its availability consequently affects this microbial ecosystem. The aim of this review is to provide further insights into the complex relationship between iron and gut microbiota. Given that overcoming anemia caused by iron deficiency is still a challenge today, gut microbiota could help identify more efficient ways to tackle this public health problem.