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Candidalysins are a new family of cytolytic fungal peptide toxins

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Jon P. Richardson, Rhys Brown, Nessim Rodriguez, Sejeong Lee, Emily Priest, Selene Mogavero, Corinne Maufrais, Don Wickramasinghe, Antzela Tsavoua, Natalia Kotowicz, Olivia Hepworth, Ana Gallego Cortes, Nicole O. Ponde, Jemima Ho, Dave L. Moyes, Duncan Wilson, Christophe D'Enfert, Bernhard Hube, Julian R. Naglik

Original languageEnglish
Article numbere03510
JournalMbio
Volume13
Issue number1
Early online date25 Jan 2022
DOIs
Accepted/In press23 Dec 2021
E-pub ahead of print25 Jan 2022
Published1 Feb 2022

Bibliographical note

Funding Information: This work was supported by grants from The Wellcome Trust (214229_Z_18_Z), the Biotechnology & Biological Sciences Research Council (BB/N014677/1), the National Institutes of Health (DE022550), and the NIH Research at Guys and St. Thomas’s NHS Foundation Trust and the King’s College London Biomedical Research Centre (IS-BRC-1215-20006) to J.R.N. D.W. is supported by a Wellcome Trust senior research fellowship (214317/A/18/Z), the MRC, and the University of Exeter (MR/N006364/2). S.M. and B.H. are supported by The Wellcome Trust (215599/Z/19/Z). B.H. is also supported by German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) project number HU 528/20-1, Ece1-Peptides, and the Cluster of Excellence Balance of the Microverse under Germany’s Excellence Strategy, EXC 2051, project identifier 390713860. C.D. received funding from the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence, Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID) and the Swiss National Science Foundation (grant CRSII5_173863). This research was funded in whole, or in part, by the Wellcome Trust (214229_Z_18_Z, 214317/A/18/Z, 215599/Z/19/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: Copyright © 2022 Richardson et al.

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Abstract

Candidalysin is the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is secreted by Candida albicans and is critical for driving infection and host immune responses in several model systems. However, Candida infections are also caused by non-C. albicans species. Here, we identify and characterize orthologs of C. albicans candidalysin in C. dubliniensis and C. tropicalis. The candidalysins have different amino acid sequences, are amphipathic, and adopt a predominantly α-helical secondary structure in solution. Comparative functional analysis demonstrates that each candidalysin causes epithelial damage and calcium influx and activates intracellular signaling pathways and cytokine secretion. Importantly, C. dubliniensis and C. tropicalis candidalysins have higher damaging and activation potential than C. albicans candidalysin and exhibit more rapid membrane binding and disruption, although both fungal species cause less damage to epithelial cells than C. albicans. This study identifies the first family of peptide cytolysins in human-pathogenic fungi.
IMPORTANCE Pathogenic fungi kill an estimated 1.5 million people every year. Recently, we discovered that the fungal pathogen Candida albicans secretes a peptide toxin called candidalysin during mucosal infection. Candidalysin causes damage to host cells, a process that supports disease progression. However, fungal infections are also caused by Candida species other than C. albicans. In this work, we identify and characterize two additional candidalysin toxins present in the related fungal pathogens C. dubliniensis and C. tropicalis. While the three candidalysins have different amino acid sequences, all three toxins are α-helical and amphipathic. Notably, the candidalysins from C. dubliniensis and C. tropicalis are more potent at inducing cell damage, calcium influx, mitogen-activated protein kinase signaling, and cytokine responses than C. albicans candidalysin, with the C. dubliniensis candidalysin having the most rapid membrane binding kinetics. These observations identify the candidalysins as the first family of peptide toxins in human-pathogenic fungi.

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