Heparin interacts with candidalysin and neutralizes its cytotoxicity to oral epithelial cells

Domae, Eisuke; Kamada, Aiko; Yoshikawa, Yusuke; Ikeo, Takashi

doi:10.1016/j.job.2023.03.002

Cited by 3 publications

(2 citation statements)

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“…Candidalysin displays a net positive charge at physiological pH due to the three lysine residues in its C-terminus 1,45 . Several publications have demonstrated that the cytotoxicity of candidalysin can be mitigated by negatively charged molecules such as albumin, heparin, and polyacrylic acid [45][46][47] . In contrast, we found that the negatively charged hyaluronic acid and alginitic acid failed to protect cells from candidalysin-induced damage.…”

Section: Discussionmentioning

confidence: 99%

“…Candidalysin displays a net positive charge at physiological pH due to the three lysine residues in its C-terminus 1,45 . Several publications have demonstrated that the cytotoxicity of candidalysin can be mitigated by negatively charged molecules such as albumin, heparin, and polyacrylic acid 45–47 . In contrast, we found that the negatively charged hyaluronic acid and alginitic acid failed to protect cells from candidalysin-induced damage.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…Candidalysin displays a net positive charge at physiological pH due to the three lysine residues in its C-terminus 1,45 . Several publications have demonstrated that the cytotoxicity of candidalysin can be mitigated by negatively charged molecules such as albumin, heparin, and polyacrylic acid 45–47 . In contrast, we found that the negatively charged hyaluronic acid and alginitic acid failed to protect cells from candidalysin-induced damage.…”

Section: Discussionmentioning

confidence: 99%