A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.
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...
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2021
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oai:doaj.org-article:b3e2ce06c5484147bdbc2ffbdee60a642021-12-02T20:00:11ZA variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.1553-73661553-737410.1371/journal.ppat.1009884https://doaj.org/article/b3e2ce06c5484147bdbc2ffbdee60a642021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009884https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Vulvovaginal 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.Junyan LiuHubertine M E WillemsEmily A SansevereStefanie AllertKatherine S BarkerDavid J LowesAndrew C DixsonZhenbo XuJian MiaoChristian DeJarnetteHelene TournuGlen E PalmerJonathan P RichardsonFrancisco N BarreraBernhard HubeJulian R NaglikBrian M PetersPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009884 (2021) |
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DOAJ |
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EN |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Junyan Liu Hubertine M E Willems Emily A Sansevere Stefanie Allert Katherine S Barker David J Lowes Andrew C Dixson Zhenbo Xu Jian Miao Christian DeJarnette Helene Tournu Glen E Palmer Jonathan P Richardson Francisco N Barrera Bernhard Hube Julian R Naglik Brian M Peters A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| description |
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. |
| format |
article |
| author |
Junyan Liu Hubertine M E Willems Emily A Sansevere Stefanie Allert Katherine S Barker David J Lowes Andrew C Dixson Zhenbo Xu Jian Miao Christian DeJarnette Helene Tournu Glen E Palmer Jonathan P Richardson Francisco N Barrera Bernhard Hube Julian R Naglik Brian M Peters |
| author_facet |
Junyan Liu Hubertine M E Willems Emily A Sansevere Stefanie Allert Katherine S Barker David J Lowes Andrew C Dixson Zhenbo Xu Jian Miao Christian DeJarnette Helene Tournu Glen E Palmer Jonathan P Richardson Francisco N Barrera Bernhard Hube Julian R Naglik Brian M Peters |
| author_sort |
Junyan Liu |
| title |
A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| title_short |
A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| title_full |
A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| title_fullStr |
A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| title_full_unstemmed |
A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. |
| title_sort |
variant ece1 allele contributes to reduced pathogenicity of candida albicans during vulvovaginal candidiasis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/b3e2ce06c5484147bdbc2ffbdee60a64 |
| work_keys_str_mv |
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