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      Candidalysin is a fungal peptide toxin critical for mucosal infection

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          Abstract

          Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Until now human pathogenic fungi were not known to possess such toxins. Here we identify the first fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signaling pathway and activates epithelial immunity. Toxin-mediated membrane permeabilization is enhanced by a positively charged C-terminus and triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name ‘Candidalysin’ for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.

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          Most cited references 97

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          Nonfilamentous C. albicans mutants are avirulent.

          Candida albicans and Saccharomyces cerevisiae switch from a yeast to a filamentous form. In Saccharomyces, this switch is controlled by two regulatory proteins, Ste12p and Phd1p. Single-mutant strains, ste12/ste12 or phd1/phd1, are partially defective, whereas the ste12/ste12 phd1/phd1 double mutant is completely defective in filamentous growth and is noninvasive. The equivalent cph1/cph1 efg1/efg1 double mutant in Candida (Cph1p is the Ste12p homolog and Efg1p is the Phd1p homolog) is also defective in filamentous growth, unable to form hyphae or pseudohyphae in response to many stimuli, including serum or macrophages. This Candida cph1/cph1 efg1/efg1 double mutant, locked in the yeast form, is avirulent in a mouse model.
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            Isogenic strain construction and gene mapping in Candida albicans.

            Genetic manipulation of Candida albicans is constrained by its diploid genome and asexual life cycle. Recessive mutations are not expressed when heterozygous and undesired mutations introduced in the course of random mutagenesis cannot be removed by genetic back-crossing. To circumvent these problems, we developed a genotypic screen that permitted identification of a heterozygous recessive mutation at the URA3 locus. The mutation was introduced by targeted mutagenesis, homologous integration of transforming DNA, to avoid introduction of extraneous mutations. The ura3 mutation was rendered homozygous by a second round of transformation resulting in a Ura- strain otherwise isogenic with the parental clinical isolate. Subsequent mutation of the Ura- strain was achieved by targeted mutagenesis using the URA3 gene as a selectable marker. URA3 selection was used repeatedly for the sequential introduction of mutations by flanking the URA3 gene with direct repeats of the Salmonella typhimurium hisG gene. Spontaneous intrachromosomal recombination between the flanking repeats excised the URA3 gene restoring a Ura- phenotype. These Ura- segregants were selected on 5-fluoroorotic acid-containing medium and used in the next round of mutagenesis. To permit the physical mapping of disrupted genes, the 18-bp recognition sequence of the endonuclease I-SceI was incorporated into the hisG repeats. Site-specific cleavage of the chromosome with I-SceI revealed the position of the integrated sequences.
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              Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog.

               Lara Kohler,  G Fink,  H. Liu (1994)
              A Candida albicans gene (CPH1) was cloned that encodes a protein homologous to Saccharomyces cerevisiae Ste12p, a transcription factor that is the target of the pheromone response mitogen-activated protein kinase cascade. CPH1 complements both the mating defect of ste12 haploids and the filamentous growth defect of ste12/ste12 diploids. Candida albicans strains without a functional CPH1 gene (cph1/cph1) show suppressed hyphal formation on solid medium. However, cph1/cph1 strains can still form hyphae in liquid culture and in response to serum. Thus, filamentous growth may be activated in C. albicans by the same signaling kinase cascade that activates Ste12p in S. cerevisiae; however, alternative pathways may exist in C. albicans.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                5 April 2016
                30 March 2016
                7 April 2016
                07 October 2016
                : 532
                : 7597
                : 64-68
                Affiliations
                [1 ]Mucosal & Salivary Biology Division, Dental Institute, King’s College London, UK
                [2 ]Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany
                [3 ]Research Center Borstel, Division of Biophysics, Borstel, Germany
                [4 ]Deutsches Elektronen-Synchrotron DESY, Hamburg, Germany
                [5 ]Department of Molecular & Biomedical Sciences, University of Maine, Orono, ME, USA
                [6 ]Wolfson CARD, King’s College, Guy’s Campus, London, UK
                [7 ]Research Group Microbial Immunology, Hans Knöll Institute, Jena, Germany
                [8 ]Centre for Ultrastructural Imaging, King’s College London, UK
                [9 ]Department of Life Sciences, Imperial College London, London, UK
                [10 ]Septomics Research Center, Hans-Knöll Institute and Friedrich Schiller University, Jena
                [11 ]Department of Molecular and Applied Microbiology, Hans Knöll Institute, Jena, Germany
                [12 ]Institute for Medical Microbiology, University Medical Center Göttingen, Göttingen, Germany
                [13 ]Friedrich Schiller University, Jena, Germany
                [14 ]Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena, Germany
                Author notes
                Current address:
                [ǂ]

                Aberdeen Fungal Group, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

                [ǂǂ]

                NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK

                [ǂǂǂ]

                ERI Biotecmed & Microbiology and Ecology Department, University of Valencia, Valencia, Spain

                Article
                EMS67371
                10.1038/nature17625
                4851236
                27027296
                ba97187a-b790-4642-ae3e-df644d6eda17

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