Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis

Valentine, Marisa; Rudolph, Paul; Dietschmann, Axel; Tsavou, Antzela; Mogavero, Selene; Lee, Sejeong; Priest, Emily L.; Zhurgenbayeva, Gaukhar; Jablonowski, Nadja; Timme, Sandra; Eggeling, Christian; Allert, Stefanie; Dolk, Edward; Naglik, Julian R.; Figge, Marc T.; Gresnigt, Mark S.; Hube, Bernhard

doi:10.1128/mbio.03409-23

Cited by 6 publications

(3 citation statements)

References 68 publications

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“…To investigate this possibility, we assessed the extent of damage caused by C. albicans to TR146 epithelial cells in the presence or absence of dextran sulfate. To facilitate comparison with previous studies 1,3,33,34 , we measured the extent of epithelial cell damage using an LDH release assay. As shown in Figs.…”

Section: Resultsmentioning

confidence: 99%

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A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage byCandida albicans

Lin,

Miao,

Schaefer

et al. 2024

Preprint

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Candidalysin is a cytolytic peptide produced by the opportunistic fungal pathogenCandida albicans. This peptide is a key virulence factor in mouse models of mucosal and hematogenously disseminated candidiasis. Despite intense interest in the role of candidalysin inC. albicanspathogenicity, its host cell targets have remained elusive. To fill this knowledge gap, we performed a genome-wide loss-of-function CRISPR screen in a human oral epithelial cell line to identify specific host factors required for susceptibility to candidalysin-induced cellular damage. Among the top hits wereXYLT2, B3GALT6 and B3GAT3, genes that function in glycosaminoglycan (GAG) biosynthesis. Deletion of these genes led to the absence of GAGs such as heparan sulfate on the epithelial cell surface and increased resistance to damage induced by both candidalysin and liveC. albicans. Biophysical analyses including surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin physically binds to sulfated GAGs, facilitating its oligomerization or enrichment on the host cell surface. The addition of exogenous sulfated GAGs or the GAG analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate, but not non-sulfated dextran, also inhibited epithelial cell endocytosis ofC. albicansand fungal-induced epithelial cell cytokine and chemokine production. In a murine model of vulvovaginal candidiasis, topical dextran sulfate administration reduced host tissue damage and decreased intravaginal IL-1β and neutrophil levels. Collectively, these data indicate that GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

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Section: Resultsmentioning

confidence: 99%

“…The copyright holder for this preprint (which this version posted May 23, 2024. ; https://doi.org/10.1101/2024.05.23.595417 doi: bioRxiv preprint previous studies 1,3,33,34 , we measured the extent of epithelial cell damage using an LDH release assay. As shown in Figs.…”

Section: Gags Are Required For Maximal Epithelial Cell Invasion Damag...mentioning

confidence: 99%

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage byCandida albicans

Lin,

Miao,

Schaefer

et al. 2024

Preprint

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“…Promising recent data suggest that targeting candidalysin through innovative therapies could interrupt the hyperinflammatory loop that drives VVC immunopathology and the severity of symptoms [71].…”

Section: Treatment Lines For Vvc In Pregnancymentioning

confidence: 99%

Candidiasis in Pregnancy: Relevant Aspects of the Pathology for the Mother and the Fetus and Therapeutic Strategies

Messina,

Mariani,

Brandolisio

et al. 2024

TropicalMed

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Vulvovaginal candidiasis (VVC) is a common condition that can lead to significant discomfort, affecting approximately 70–75% of women at least once in their lives. During pregnancy, the prevalence of VVC is estimated to be around 20%, peaking at about 30% in the third trimester, with a number of specific risk factors predisposing to yeast infection being identified and needing elucidation. This review aims to provide updated knowledge on candidiasis during pregnancy, addressing risk factors and maternal and neonatal outcomes, as well as discussing optimal therapeutic strategies to safeguard mothers and newborns. The bibliographic search involved two biomedical databases, PubMed and Embase, without imposing time limits. Among all Candida spp., Candida albicans remains the most frequent causative species. The hyperestrogenic environment of the vaginal mucosa and reduced immune defenses, physiological effects of pregnancy, create conditions favorable for Candida spp. vaginal colonization and hence VVC. Recent evidence shows an association between VVC and adverse obstetric outcomes, including premature membrane rupture (PROM), chorioamnionitis, preterm birth, and puerperal infections. Prompt and effective management of this condition is therefore crucial to prevent adverse obstetric outcomes, maternal–fetal transmission, and neonatal disease. Additional studies are required to confirm the benefits of systemic treatment for maternal candida infection or colonization in preventing premature birth or neonatal systemic candidiasis.

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Epithelial responses to fungal pathogens

Mills,

Aufiero,

Hohl

2024

Current Opinion in Microbiology

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Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis

Cited by 6 publications

References 68 publications

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage byCandida albicans

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage byCandida albicans

Candidiasis in Pregnancy: Relevant Aspects of the Pathology for the Mother and the Fetus and Therapeutic Strategies

Epithelial responses to fungal pathogens

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