Candida albicans induces neutrophil extracellular traps and leucotoxic hypercitrullination via candidalysin

Author:

Unger Lucas12ORCID,Skoluda Samuel12ORCID,Backman Emelie12ORCID,Amulic Borko3ORCID,Ponce‐Garcia Fernando M3ORCID,Etiaba Chinelo NC3,Yellagunda Sujan12,Krüger Renate4,von Bernuth Horst4567ORCID,Bylund Johan8ORCID,Hube Bernhard910,Naglik Julian R11ORCID,Urban Constantin F12ORCID

Affiliation:

1. Department of Clinical Microbiology Umeå University Umeå Sweden

2. Umeå Centre for Microbial Research (UCMR) Umeå University Umeå Sweden

3. School of Cellular and Molecular Medicine University of Bristol Bristol UK

4. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine Charité – Universitätsmedizin Berlin Berlin Germany

5. Department of Immunology Labor Berlin Labor Berlin – Charité Vivantes GmbH Berlin Germany

6. Berlin Institute of Health at Charité – Universitätsmedizin Berlin Berlin Germany

7. Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health (BIH) Berlin‐Brandenburg Center for Regenerative Therapies (BCRT) Berlin Germany

8. Department of Oral Microbiology & Immunology, Institute of Odontology Sahlgrenska Academy at University of Gothenburg Gothenburg Sweden

9. Department of Microbial Pathogenicity Mechanisms Leibniz Institute for Natural Product Research and Infection Biology ‐ Hans‐Knoell‐Institute Jena Germany

10. Friedrich Schiller University Jena Germany

11. Centre for Host‐Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences King's College London London UK

Abstract

AbstractThe peptide toxin candidalysin, secreted by Candida albicans hyphae, promotes stimulation of neutrophil extracellular traps (NETs). However, candidalysin alone triggers a distinct mechanism for NET‐like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leucotoxic hypercitrullination, which is governed by calcium‐induced protein arginine deaminase 4 activation and initiation of intracellular signalling events in a dose‐ and time‐dependent manner. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin‐dependent kinases that are crucial for NET release. Candidalysin‐triggered NLS demonstrate anti‐Candida activity, which is resistant to nuclease treatment and dependent on the deprivation of Zn2+. This study reveals that C. albicans hyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entangles C. albicans hyphae and efficiently inhibits their growth.

Funder

National Institutes of Health

Hjärt-Lungfonden

Kempestiftelserna

Scandinavian Society for Antimicrobial Chemotherapy Foundation

Stiftelsen Konung Gustaf V:s 80-årsfond

Vetenskapsrådet

Wellcome Trust

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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