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A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC8432879 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

Liu Junyan J Willems Hubertine M E HME Sansevere Emily A EA Allert Stefanie S Barker Katherine S KS Lowes David J DJ Dixson Andrew C AC Xu Zhenbo Z Miao Jian J DeJarnette Christian C Tournu Helene H Palmer Glen E GE Richardson Jonathan P JP Barrera Francisco N FN Hube Bernhard B Naglik Julian R JR Peters Brian M BM

PLoS pathogens 20210910 9

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 clinic ...[more]

PMID: 34506615

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Project description:Candidiasis affects a wide variety of immunocompromised and medically compromised patients. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, which were genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo Unexpectedly, both strains showed a dramatic reduction in organ fungal burden in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling generally did not reveal any significant changes in the host response to UME6 expression in the NACS that could explain the increased clearance of infection. Interestingly, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly downregulated. These findings suggest that there are fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicansIMPORTANCE Many immunocompromised individuals, including HIV/AIDS and cancer patients, are susceptible to candidiasis. About half of all cases are caused by the major fungal pathogen Candida albicans, whereas the remainder are due to less pathogenic non-albicans Candida species (NACS). Generation of filamentous cells represents a major virulence property of C. albicans, and the NACS are believed to be less pathogenic, in part, because they do not filament as well as C. albicans does. To address this question, we determined the pathogenicity of two NACS strains that have been genetically engineered to promote filamentation during infection. Surprisingly, these strains showed a dramatic reduction in pathogenicity. The host immune response did not appear to be affected. However, unlike C. albicans, filamentation of the NACS was associated with downregulation of several genes important for pathogenicity processes. Our results suggest that there are fundamental evolutionary differences in the relationship between filamentation and pathogenesis in NACS compared to C. albicans.

Dataset Information

A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

Publications

A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

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