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A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis
- Source :
- PLoS Pathogens, Vol 17, Iss 9, p e1009884 (2021), PLoS Pathogens
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Vulvovaginal candidiasis (VVC), caused primarily by the human fungal pathogen Candida albicans, results in significant quality-of-life issues for women worldwide. Candidalysin, a toxin derived from a polypeptide (Ece1p) encoded by the ECE1 gene, plays a crucial role in driving immunopathology at the vaginal mucosa. This study aimed to determine if expression and/or processing of Ece1p differs across C. albicans isolates and whether this partly underlies differential pathogenicity observed clinically. Using a targeted sequencing approach, we determined that isolate 529L harbors a similarly expressed, yet distinct Ece1p isoform variant that encodes for a predicted functional candidalysin; this isoform was conserved amongst a collection of clinical isolates. Expression of the ECE1 open reading frame (ORF) from 529L in an SC5314-derived ece1Δ/Δ strain resulted in significantly reduced vaginopathogenicity as compared to an isogenic control expressing a wild-type (WT) ECE1 allele. However, in vitro challenge of vaginal epithelial cells with synthetic candidalysin demonstrated similar toxigenic activity amongst SC5314 and 529L isoforms. Creation of an isogenic panel of chimeric strains harboring swapped Ece1p peptides or HiBiT tags revealed reduced secretion with the ORF from 529L that was associated with reduced virulence. A genetic survey of 78 clinical isolates demonstrated a conserved pattern between Ece1p P2 and P3 sequences, suggesting that substrate specificity around Kex2p-mediated KR cleavage sites involved in protein processing may contribute to differential pathogenicity amongst clinical isolates. Therefore, we present a new mechanism for attenuation of C. albicans virulence at the ECE1 locus.<br />Author summary Vulvovaginal candidiasis (VVC), caused primarily by the human fungal pathogen Candida albicans, results in significant quality-of-life issues for women worldwide. Candidalysin, a toxin derived from a polypeptide (Ece1p) encoded by the ECE1 gene, plays a crucial role in driving disease pathology. In this study, we aimed to determine if genetic variation of ECE1 existed across a collection of C. albicans clinical isolates. Using a targeted sequencing approach, we identified a conserved variant candidalysin isoform. We then constructed isogenic chimeric strains harboring swapped Ece1p peptides or HiBiT tags between representative isoforms and showed impaired secretion with the variant that was associated with reduced virulence in vitro and in vivo. We also elucidated a conserved pattern between key sequences near lysine-arginine cleavage sites involved in Ece1p polypeptide processing by the Kex2p enzyme that correlate with predicted and experimental candidalysin secretion. Therefore, we present a novel mechanism for attenuation of C. albicans virulence at the ECE1 locus that may partly underlie differential clinical outcomes and contribute to the balance between commensal and pathogen at the vaginal mucosa.
- Subjects :
- Physiology
Yeast and Fungal Models
Pathogenesis
Pathology and Laboratory Medicine
Epithelium
Mice
Animal Cells
Candida albicans
Medicine and Health Sciences
Biology (General)
Candida
Fungal Pathogens
0303 health sciences
Virulence
biology
Eukaryota
Animal Models
Genomics
Corpus albicans
3. Good health
Experimental Organism Systems
Medical Microbiology
Female
Pathogens
Cellular Types
Anatomy
Candidalysin
Research Article
Virulence Factors
QH301-705.5
Immunology
Mouse Models
Locus (genetics)
Mycology
Immunopathology
Research and Analysis Methods
Microbiology
Fungal Proteins
03 medical and health sciences
Model Organisms
Virology
Genetics
Animals
Humans
Allele
Gene Prediction
Microbial Pathogens
Molecular Biology
Gene
Alleles
Candidiasis, Vulvovaginal
Secretion
030304 developmental biology
030306 microbiology
Organisms
Fungi
Genetic Variation
Biology and Life Sciences
Computational Biology
Epithelial Cells
Cell Biology
RC581-607
Genome Analysis
biology.organism_classification
Yeast
Open reading frame
Biological Tissue
Animal Studies
Clinical Immunology
Parasitology
Clinical Medicine
Immunologic diseases. Allergy
Physiological Processes
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 17
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....5540c6efd61dc51cb2045f29d6cd489e