A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains
ABSTRACT Vulvovaginal candidiasis (VVC) affects nearly 3/4 of women during their lifetime, and its symptoms seriously reduce quality of life. Although Candida albicans is a common commensal, it is unknown if VVC results from a switch from a commensal to pathogenic state, if only some strains can cau...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00107-23 |
| _version_ | 1797839583115739136 |
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| author | Arianna Sala Andrea Ardizzoni Luca Spaggiari Nikhil Vaidya Jane van der Schaaf Cosmeri Rizzato Claudio Cermelli Selene Mogavero Thomas Krüger Maximilian Himmel Olaf Kniemeyer Axel A. Brakhage Benjamin L. King Antonella Lupetti Manola Comar Francesco de Seta Arianna Tavanti Elisabetta Blasi Robert T. Wheeler Eva Pericolini |
| author_facet | Arianna Sala Andrea Ardizzoni Luca Spaggiari Nikhil Vaidya Jane van der Schaaf Cosmeri Rizzato Claudio Cermelli Selene Mogavero Thomas Krüger Maximilian Himmel Olaf Kniemeyer Axel A. Brakhage Benjamin L. King Antonella Lupetti Manola Comar Francesco de Seta Arianna Tavanti Elisabetta Blasi Robert T. Wheeler Eva Pericolini |
| author_sort | Arianna Sala |
| collection | DOAJ |
| description | ABSTRACT Vulvovaginal candidiasis (VVC) affects nearly 3/4 of women during their lifetime, and its symptoms seriously reduce quality of life. Although Candida albicans is a common commensal, it is unknown if VVC results from a switch from a commensal to pathogenic state, if only some strains can cause VVC, and/or if there is displacement of commensal strains with more pathogenic strains. We studied a set of VVC and colonizing C. albicans strains to identify consistent in vitro phenotypes associated with one group or the other. We find that the strains do not differ in overall genetic profile or behavior in culture media (i.e., multilocus sequence type [MLST] profile, rate of growth, and filamentation), but they show strikingly different behaviors during their interactions with vaginal epithelial cells. Epithelial infections with VVC-derived strains yielded stronger fungal proliferation and shedding of fungi and epithelial cells. Transcriptome sequencing (RNA-seq) analysis of representative epithelial cell infections with selected pathogenic or commensal isolates identified several differentially activated epithelial signaling pathways, including the integrin, ferroptosis, and type I interferon pathways; the latter has been implicated in damage protection. Strikingly, inhibition of type I interferon signaling selectively increases fungal shedding of strains in the colonizing cohort, suggesting that increased shedding correlates with lower interferon pathway activation. These data suggest that VVC strains may intrinsically have enhanced pathogenic potential via differential elicitation of epithelial responses, including the type I interferon pathway. Therefore, it may eventually be possible to evaluate pathogenic potential in vitro to refine VVC diagnosis. IMPORTANCE Despite a high incidence of VVC, we still have a poor understanding of this female-specific disease whose negative impact on women’s quality of life has become a public health issue. It is not yet possible to determine by genotype or laboratory phenotype if a given Candida albicans strain is more or less likely to cause VVC. Here, we show that Candida strains causing VVC induce more fungal shedding from epithelial cells than strains from healthy women. This effect is also accompanied by increased epithelial cell detachment and differential activation of the type I interferon pathway. These distinguishing phenotypes suggest it may be possible to evaluate the VVC pathogenic potential of fungal isolates. This would permit more targeted antifungal treatments to spare commensals and could allow for displacement of pathogenic strains with nonpathogenic colonizers. We expect these new assays to provide a more targeted tool for identifying fungal virulence factors and epithelial responses that control fungal vaginitis. |
| first_indexed | 2024-04-09T16:00:17Z |
| format | Article |
| id | doaj.art-0f04dab6756f43c9bb3b3df5ba431384 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T16:00:17Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-0f04dab6756f43c9bb3b3df5ba4313842023-04-25T13:04:57ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00107-23A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated StrainsArianna Sala0Andrea Ardizzoni1Luca Spaggiari2Nikhil Vaidya3Jane van der Schaaf4Cosmeri Rizzato5Claudio Cermelli6Selene Mogavero7Thomas Krüger8Maximilian Himmel9Olaf Kniemeyer10Axel A. Brakhage11Benjamin L. King12Antonella Lupetti13Manola Comar14Francesco de Seta15Arianna Tavanti16Elisabetta Blasi17Robert T. Wheeler18Eva Pericolini19Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, ItalyClinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USADepartment of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USADepartment of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyDepartment of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, GermanyDepartment of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, GermanyDepartment of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, GermanyDepartment of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, GermanyDepartment of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, GermanyDepartment of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USADepartment of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyInstitute for Maternal and Child Health—IRCCS Burlo Garofolo, Trieste, ItalyInstitute for Maternal and Child Health—IRCCS Burlo Garofolo, Trieste, ItalyDepartment of Biology, University of Pisa, Pisa, ItalyDepartment of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USADepartment of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, ItalyABSTRACT Vulvovaginal candidiasis (VVC) affects nearly 3/4 of women during their lifetime, and its symptoms seriously reduce quality of life. Although Candida albicans is a common commensal, it is unknown if VVC results from a switch from a commensal to pathogenic state, if only some strains can cause VVC, and/or if there is displacement of commensal strains with more pathogenic strains. We studied a set of VVC and colonizing C. albicans strains to identify consistent in vitro phenotypes associated with one group or the other. We find that the strains do not differ in overall genetic profile or behavior in culture media (i.e., multilocus sequence type [MLST] profile, rate of growth, and filamentation), but they show strikingly different behaviors during their interactions with vaginal epithelial cells. Epithelial infections with VVC-derived strains yielded stronger fungal proliferation and shedding of fungi and epithelial cells. Transcriptome sequencing (RNA-seq) analysis of representative epithelial cell infections with selected pathogenic or commensal isolates identified several differentially activated epithelial signaling pathways, including the integrin, ferroptosis, and type I interferon pathways; the latter has been implicated in damage protection. Strikingly, inhibition of type I interferon signaling selectively increases fungal shedding of strains in the colonizing cohort, suggesting that increased shedding correlates with lower interferon pathway activation. These data suggest that VVC strains may intrinsically have enhanced pathogenic potential via differential elicitation of epithelial responses, including the type I interferon pathway. Therefore, it may eventually be possible to evaluate pathogenic potential in vitro to refine VVC diagnosis. IMPORTANCE Despite a high incidence of VVC, we still have a poor understanding of this female-specific disease whose negative impact on women’s quality of life has become a public health issue. It is not yet possible to determine by genotype or laboratory phenotype if a given Candida albicans strain is more or less likely to cause VVC. Here, we show that Candida strains causing VVC induce more fungal shedding from epithelial cells than strains from healthy women. This effect is also accompanied by increased epithelial cell detachment and differential activation of the type I interferon pathway. These distinguishing phenotypes suggest it may be possible to evaluate the VVC pathogenic potential of fungal isolates. This would permit more targeted antifungal treatments to spare commensals and could allow for displacement of pathogenic strains with nonpathogenic colonizers. We expect these new assays to provide a more targeted tool for identifying fungal virulence factors and epithelial responses that control fungal vaginitis.https://journals.asm.org/doi/10.1128/mbio.00107-23Candida albicansepithelial cellshost-pathogen interactionsinterferonsvulvovaginal candidiasis |
| spellingShingle | Arianna Sala Andrea Ardizzoni Luca Spaggiari Nikhil Vaidya Jane van der Schaaf Cosmeri Rizzato Claudio Cermelli Selene Mogavero Thomas Krüger Maximilian Himmel Olaf Kniemeyer Axel A. Brakhage Benjamin L. King Antonella Lupetti Manola Comar Francesco de Seta Arianna Tavanti Elisabetta Blasi Robert T. Wheeler Eva Pericolini A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains mBio Candida albicans epithelial cells host-pathogen interactions interferons vulvovaginal candidiasis |
| title | A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains |
| title_full | A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains |
| title_fullStr | A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains |
| title_full_unstemmed | A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains |
| title_short | A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains |
| title_sort | new phenotype in candida epithelial cell interaction distinguishes colonization versus vulvovaginal candidiasis associated strains |
| topic | Candida albicans epithelial cells host-pathogen interactions interferons vulvovaginal candidiasis |
| url | https://journals.asm.org/doi/10.1128/mbio.00107-23 |
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