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      A Novel Hybrid Iron Regulation Network Combines Features from Pathogenic and Nonpathogenic Yeasts

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          ABSTRACT

          Iron is an essential micronutrient for both pathogens and their hosts, which restrict iron availability during infections in an effort to prevent microbial growth. Successful human pathogens like the yeast Candida glabrata have thus developed effective iron acquisition strategies. Their regulation has been investigated well for some pathogenic fungi and in the model organism Saccharomyces cerevisiae, which employs an evolutionarily derived system. Here, we show that C. glabrata uses a regulation network largely consisting of components of the S. cerevisiae regulon but also of elements of other pathogenic fungi. Specifically, similarly to baker’s yeast, Aft1 is the main positive regulator under iron starvation conditions, while Cth2 degrades mRNAs encoding iron-requiring enzymes. However, unlike the case with S. cerevisiae, a Sef1 ortholog is required for full growth under iron limitation conditions, making C. glabrata an evolutionary intermediate to SEF1-dependent fungal pathogens. Therefore, C. glabrata has evolved an iron homeostasis system which seems to be unique within the pathogenic fungi.

          IMPORTANCE

          The fungus Candida glabrata represents an evolutionarily close relative of the well-studied and benign baker’s yeast and model organism Saccharomyces cerevisiae. On the other hand, C. glabrata is an important opportunistic human pathogen causing both superficial and systemic infections. The ability to acquire trace metals, in particular, iron, and to tightly regulate this process during infection is considered an important virulence attribute of a variety of pathogens. Importantly, S. cerevisiae uses a highly derivative regulatory system distinct from those of other fungi. Until now, the regulatory mechanism of iron homeostasis in C. glabrata has been mostly unknown. Our study revealed a hybrid iron regulation network that is unique to C. glabrata and is placed at an evolutionary midpoint between those of S. cerevisiae and related fungal pathogens. We thereby show that, in the host, even a successful human pathogen can rely largely on a strategy normally found in nonpathogenic fungi from a terrestrial environment.

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          Most cited references61

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          Iron and microbial infection.

          The use of iron as a cofactor in basic metabolic pathways is essential to both pathogenic microorganisms and their hosts. It is also a pivotal component of the innate immune response through its role in the generation of toxic oxygen and nitrogen intermediates. During evolution, the shared requirement of micro- and macroorganisms for this important nutrient has shaped the pathogen-host relationship. Here, we discuss how pathogens compete with the host for iron, and also how the host uses iron to counteract this threat.
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            Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells.

            The ferrozine-based colorimetric assay described here permits the quantitation of iron in cultured cells in amounts ranging between 0.2 and 30 nmol. Ferrous and ferric iron were detected equally well by the assay and the accuracy was unaffected by other divalent metal cations. This colorimetric assay was used to study iron accumulation in brain astrocytes that had been cultured in 24-well dishes. Iron complexed to cellular proteins was made accessible to ferrozine by treatment of cell lysates with acidic KMnO(4) solution. The basal amounts of iron in untreated astrocyte cultures were approximately 10 nmol iron per mg protein. Incubation of the cells with ferric ammonium citrate caused the total cellular iron content to increase in a concentration-dependent manner. The estimates of cellular iron content that were obtained with the ferrozine-based assay did not differ from those determined by atomic absorption spectroscopy. The colorimetric assay described here provides a sensitive, cheap, and reliable method for the quantitation of intracellular iron and for the investigation of iron accumulation in cultured cells.
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              Siderophores in fungal physiology and virulence.

              Maintaining the appropriate balance of iron between deficiency and toxicity requires fine-tuned control of systems for iron uptake and storage. Both among fungal species and within a single species, different systems for acquisition, storage, and regulation of iron are present. Here we discuss the most recent findings on the mechanisms involved in maintaining iron homeostasis with a focus on siderophores, low-molecular-mass iron chelators, employed for iron uptake and storage. Recently siderophores have been found to be crucial for pathogenicity of animal, as well as plant-pathogenic fungi and for maintenance of plant-fungal symbioses.
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                Author and article information

                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                18 October 2016
                Sep-Oct 2016
                : 7
                : 5
                : e01782-16
                Affiliations
                [a ]Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Department of Microbial Pathogenicity Mechanisms, Jena, Germany
                [b ]Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Research Group Systems Biology and Bioinformatics, Jena, Germany
                [c ]Friedrich Schiller University, Jena, Germany
                [d ]Center for Sepsis Control and Care (CSCC), University Hospital Jena, Jena, Germany
                Author notes
                Address correspondence to Bernhard Hube, Bernhard.Hube@ 123456leibniz-hki.de .

                S.B., L.K., and B.H. contributed equally to this article.

                Editor Michael Lorenz, University of Texas Health Science Center

                This article is a direct contribution from a Fellow of the American Academy of Microbiology. External solicited reviewers: Dennis Thiele, Duke University Medical Center; James Kronstad, University of British Columbia.

                Article
                mBio01782-16
                10.1128/mBio.01782-16
                5082906
                27795405
                46804f30-6537-4a98-a5b2-fbe37f2f78f7
                Copyright © 2016 Gerwien et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 23 September 2016
                : 29 September 2016
                Page count
                supplementary-material: 5, Figures: 7, Tables: 1, Equations: 0, References: 75, Pages: 15, Words: 11774
                Funding
                Funded by: Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659
                Award ID: HU 528/17-1
                Award ID: HU 528/16-2
                Award ID: Transregio 124
                Award Recipient : Franziska Gerwien Award Recipient : Joerg Linde Award Recipient : Lydia Kasper Award Recipient : Bernhard Hube
                Funded by: Bundesministerium für Bildung und Forschung (BMBF) http://dx.doi.org/10.13039/501100002347
                Award ID: 01EO1002
                Award Recipient : Bernhard Hube
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Custom metadata
                September/October 2016

                Life sciences
                Life sciences

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