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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. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which 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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  • 01 April 2016

    A label in Fig. 3b of the PDF file initially published online was corrupted and was replaced.

  • 07 April 2016

    A missing citation to the Extended Data Tables was corrected in the HTML on 7 April 2016.

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Acknowledgements

We thank S. Gaffen, B. Klein, C. Hertweck, A. Tucker, J. Green and S. Challacombe for comments on the manuscript. For experimental assistance, we thank S. Bevan and D. Andersson (calcium assays), D. Nayar (histology), D. Rahman and M. Mistry (murine model), M. Nilan (zebrafish model), S. Groth (FRET spectroscopy), N. Gebauer (Impedance experiments), D. Schulz (kex1∆/∆ strain) and our colleagues for supplying fungal mutant strains. This work was supported by grants from the Medical Research Council (MR/J008303/1, MR/M011372/1), Biotechnology & Biological Sciences Research Council (BB/J015261/1), FP7-PEOPLE-2013-Initial Training Network (606786) to J.R.N.; Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z) to J.R.N. and D.W.; Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102549/Z/13/Z) to D.W.; Deutsche Forschungsgemeinschaft CRC/TR124 FungiNet Project C1 and Z2, Deutsche Forschungsgemeinschaft SPP 1580 (Hu 528/17-1) and CSCC, German Federal Ministry of Education and Health (BMBF) 01EO1002 to B.Hu.; Cluster of Excellence ‘Inflammation at interfaces’ and Deutsche Forschungsgemeinschaft SPP1580 project GU 568/5-1 to T.G.; National Institutes of Health (R15AI094406) and the Burroughs Wellcome Fund to R.T.W.

Author information

Author notes

    • David L. Moyes
    • , Duncan Wilson
    • , Jonathan P. Richardson
    •  & Selene Mogavero

    These authors contributed equally to this work.

    • Duncan Wilson
    • , Manohursingh Runglall
    •  & Celia Murciano

    Present addresses: Aberdeen Fungal Group, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK (D.W.); NIHR Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 1UL, UK (M.R.); ERI Biotecmed & Microbiology and Ecology Department, University of Valencia, Valencia 46100, Spain (C.M.).

Affiliations

  1. Mucosal & Salivary Biology Division, Dental Institute, King’s College London SE1 1UL, UK

    • David L. Moyes
    • , Jonathan P. Richardson
    • , Shirley X. Tang
    • , Manohursingh Runglall
    • , Celia Murciano
    • , Mariana Blagojevic
    • , Selvam Thavaraj
    • , Simona I. Iancu
    • , Nessim Kichik
    •  & Julian R. Naglik
  2. Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, D-07745 Jena, Germany

    • Duncan Wilson
    • , Selene Mogavero
    • , Sarah Höfs
    • , Toni M. Förster
    • , Betty Hebecker
    • , Lydia Kasper
    •  & Bernhard Hube
  3. Research Center Borstel, Division of Biophysics, D-23845 Borstel, Germany

    • Julia Wernecke
    •  & Thomas Gutsmann
  4. Deutsches Elektronen-Synchrotron DESY, D-22607 Hamburg, Germany

    • Julia Wernecke
  5. Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine 04469, USA

    • Remi L. Gratacap
    •  & Robert T. Wheeler
  6. Wolfson CARD, King’s College London, Guy’s Campus, London SE1 1UL, UK

    • Jon Robbins
  7. Research Group Microbial Immunology, Hans Knöll Institute, D-07745 Jena, Germany

    • Betty Hebecker
  8. Centre for Ultrastructural Imaging, King’s College London, London SE1 1UL, UK

    • Gema Vizcay
  9. Department of Life Sciences, Imperial College London, London SW7 2AZ, UK

    • Nessim Kichik
    •  & Ernesto Cota
  10. Septomics Research Center, Hans-Knöll Institute and Friedrich Schiller University, D-07745 Jena, Germany

    • Antje Häder
    •  & Oliver Kurzai
  11. Department of Molecular and Applied Microbiology, Hans Knöll Institute, D-07745 Jena, Germany

    • Ting Luo
    • , Thomas Krüger
    •  & Olaf Kniemeyer
  12. Institute for Medical Microbiology, University Medical Center Göttingen, D-37075 Göttingen, Germany

    • Oliver Bader
  13. Friedrich Schiller University, D-07737 Jena, Germany

    • Bernhard Hube
  14. Integrated Research and Treatment Center, Center for Sepsis Control and Care, D-07747 Jena, Germany

    • Bernhard Hube

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Contributions

D.L.M., J.P.R., S.X.T., M.R., C.M., M.B., S.I.I. and N.K. performed signalling, transcription factor, calcium and cytokine assays, and murine work; D.W., S.H., S.M., T.M.F., B.He., L.K. A.H., O.B. and O.Ku. created fungal strains and performed fluorescent microscopy, adhesion, invasion, gene expression and damage assays; R.L.G. and R.T.W. performed zebrafish experiments; J.W. and T.G. performed biophysical analysis with artificial membranes; J.R. performed whole patch clamp analysis; G.V. performed electron microscopy; S.T. performed histological analysis; S.M., T.L., T.K. and O.Kn. performed LC-MS analyses; J.R.N., B.Hu., D.L.M., J.P.R. and D.W. wrote the paper; J.R.N., B.Hu. and E.C. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bernhard Hube.

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https://doi.org/10.1038/nature17625

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