Candidalysin is a fungal peptide toxin critical for mucosal infection

David L. Moyes; Duncan Wilson; Jonathan P Richardson; Selene  Mogavero; Shirley X Tang; Julia Wernecke; Sarah Hofs; Remi L Gratacap; Jon Robbins; Manohursingh Runglall; Celia Murciano; Mariana Blagojevic; Selvam Thavaraj; Toni M Forster; Betty Hebecker; Lydia Kasper; Gema Vizcay; Simona I Iancu; Nessim Kichik; Antje Hader; Oliver Kurzai; Ting Luo; Thomas Kruger; Olaf Kniemeyer; Ernesto Cota; Oliver Bader; Robert T  Wheeler; Thomas Gutsmann; Bernhard Hube; Julian R. Naglik

doi:10.1038/nature17625

Candidalysin is a fungal peptide toxin critical for mucosal infection

David L. Moyes, Duncan Wilson, Jonathan P Richardson, Selene Mogavero, Shirley X Tang, Julia Wernecke, Sarah Hofs, Remi L Gratacap, Jon Robbins, Manohursingh Runglall, Celia Murciano, Mariana Blagojevic, Selvam Thavaraj, Toni M Forster, Betty Hebecker, Lydia Kasper, Gema Vizcay, Simona I Iancu, Nessim Kichik, Antje HaderOliver Kurzai, Ting Luo, Thomas Kruger, Olaf Kniemeyer, Ernesto Cota, Oliver Bader, Robert T Wheeler, Thomas Gutsmann, Bernhard Hube, Julian R. Naglik

Medical Sciences

University of Glasgow

Research output: Contribution to journal › Article › peer-review

574 Citations (Scopus)

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.

Original language	English
Pages (from-to)	64-68
Number of pages	5
Journal	Nature
Volume	532
Early online date	30 Mar 2016
DOIs	https://doi.org/10.1038/nature17625
Publication status	Published - 7 Apr 2016

Bibliographical note

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

Keywords

antimicrobial responses
fungal host response
fungal pathogenesis

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Moyes, D. L., Wilson, D., Richardson, J. P., Mogavero, S., Tang, S. X., Wernecke, J., Hofs, S., Gratacap, R. L., Robbins, J., Runglall, M., Murciano, C., Blagojevic, M., Thavaraj, S., Forster, T. M., Hebecker, B., Kasper, L., Vizcay, G., Iancu, S. I., Kichik, N., ... Naglik, J. R. (2016). Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature, 532, 64-68. https://doi.org/10.1038/nature17625

Moyes, DL, Wilson, D, Richardson, JP, Mogavero, S, Tang, SX, Wernecke, J, Hofs, S, Gratacap, RL, Robbins, J, Runglall, M, Murciano, C, Blagojevic, M, Thavaraj, S, Forster, TM, Hebecker, B, Kasper, L, Vizcay, G, Iancu, SI, Kichik, N, Hader, A, Kurzai, O, Luo, T, Kruger, T, Kniemeyer, O, Cota, E, Bader, O, Wheeler, RT, Gutsmann, T, Hube, B & Naglik, JR 2016, 'Candidalysin is a fungal peptide toxin critical for mucosal infection', Nature, vol. 532, pp. 64-68. https://doi.org/10.1038/nature17625

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title = "Candidalysin is a fungal peptide toxin critical for mucosal infection",

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 {\textquoteleft}Candidalysin{\textquoteright} for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.",

keywords = "antimicrobial responses, fungal host response, fungal pathogenesis",

author = "Moyes, {David L.} and Duncan Wilson and Richardson, {Jonathan P} and Selene Mogavero and Tang, {Shirley X} and Julia Wernecke and Sarah Hofs and Gratacap, {Remi L} and Jon Robbins and Manohursingh Runglall and Celia Murciano and Mariana Blagojevic and Selvam Thavaraj and Forster, {Toni M} and Betty Hebecker and Lydia Kasper and Gema Vizcay and Iancu, {Simona I} and Nessim Kichik and Antje Hader and Oliver Kurzai and Ting Luo and Thomas Kruger and Olaf Kniemeyer and Ernesto Cota and Oliver Bader and Wheeler, {Robert T} and Thomas Gutsmann and Bernhard Hube and Naglik, {Julian R.}",

note = "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 {\textquoteleft}Inflammation at interfaces{\textquoteright} 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",

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doi = "10.1038/nature17625",

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T1 - Candidalysin is a fungal peptide toxin critical for mucosal infection

AU - Moyes, David L.

AU - Wilson, Duncan

AU - Richardson, Jonathan P

AU - Mogavero, Selene

AU - Tang, Shirley X

AU - Wernecke, Julia

AU - Hofs, Sarah

AU - Gratacap, Remi L

AU - Robbins, Jon

AU - Runglall, Manohursingh

AU - Murciano, Celia

AU - Blagojevic, Mariana

AU - Thavaraj, Selvam

AU - Forster, Toni M

AU - Hebecker, Betty

AU - Kasper, Lydia

AU - Vizcay, Gema

AU - Iancu, Simona I

AU - Kichik, Nessim

AU - Hader, Antje

AU - Kurzai, Oliver

AU - Luo, Ting

AU - Kruger, Thomas

AU - Kniemeyer, Olaf

AU - Cota, Ernesto

AU - Bader, Oliver

AU - Wheeler, Robert T

AU - Gutsmann, Thomas

AU - Hube, Bernhard

AU - Naglik, Julian R.

N1 - 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

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.

AB - 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.

KW - antimicrobial responses

KW - fungal host response

KW - fungal pathogenesis

U2 - 10.1038/nature17625

DO - 10.1038/nature17625

M3 - Article

SN - 0028-0836

VL - 532

SP - 64

EP - 68

JO - Nature

JF - Nature

ER -

Candidalysin is a fungal peptide toxin critical for mucosal infection

Abstract

Bibliographical note

Keywords

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