Contributors: King‘s College London; Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF); Institut Pasteur Paris (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); University College Dublin Dublin (UCD); Trinity College Dublin; Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute); Friedrich-Schiller-Universität = Friedrich Schiller University Jena Jena, Germany; We are very grateful to David Coleman (University of Dublin, Ireland) for his kind gift of fungal strains. This work was supported by a Faculty of Dentistry, Oral & Craniofacial Sciences (FoDOCs) PhD Studentship to J.P.R., the Wellcome Trust (214229_Z_18_Z) and National Institutes of Health (R37-DE022550) to J.R.N., the Agence Nationale de Recherche (ANR-10-LABX-62-IBEID) and the Swiss National Science Foundation (Sinergia CRSII5_173863/1) to C.d.E., and the Irish Research Council (no grant number) and Science Foundation Ireland 19/FFP/6668 to G.B. B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the Collaborative Research Center (CRC)/Transregio 124 "FungiNet" projects C1 and C2, and within the Cluster of Excellence “Balance of the Microverse” under Germany’s Excellence Strategy—EXC 2051—Project-ID 467 39071386.Work in the DS laboratory was supported by a gift from BNP Paribas Corporate & Investment Banking—Ireland—Business Gift 2010. E.L.P is supported by the UK Medical Research Council (MR/W006820/1) and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.; ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
نبذة مختصرة : International audience ; Candida albicans causes millions of mucosal infections in humans annually. Hyphal overgrowth on mucosal surfaces is frequently associated with tissue damage caused by candidalysin, a secreted peptide toxin that destabilizes the plasma membrane of host cells thereby promoting disease and immunopathology. Candidalysin was first identified in C. albicans strain SC5314, but recent investigations have revealed candidalysin “variants” of differing amino acid sequence in isolates of C. albicans , and the related species C. dubliniensis , and C tropicalis , suggesting that sequence variation among candidalysins may be widespread in natural populations of these Candida species. Here, we analyzed ECE1 gene sequences from 182 C . albicans isolates, 10 C . dubliniensis isolates, and 78 C . tropicalis isolates and identified 10, 3, and 2 candidalysin variants in these species, respectively. Application of candidalysin variants to epithelial cells revealed differences in the ability to cause cellular damage, changes in metabolic activity, calcium influx, MAPK signalling, and cytokine secretion, while biophysical analyses indicated that variants exhibited differences in their ability to interact with and permeabilize a membrane. This study identifies candidalysin variants with differences in biological activity that are present in medically relevant Candida species. IMPORTANCE Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis , thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin “variant” toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans , C. dubliniensis , and C. tropicalis and identified candidalysin ...
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