Abstract
Candida albicans is maintained as a commensal by immune mechanisms at the oral epithelia. Oral antifungal peptide Histatin 5 (Hst 5) may function in innate immunity, but the specific role Hst 5 plays in C. albicans commensalism is unclear. Since Zn-binding potentiates the candidacidal activity of Hst 5, we hypothesized that Hst 5+Zn would elicit a unique fungal stress response to shape interactions between C. albicans and oral epithelial cells (OECs). We found that Hst 5+Zn but not Hst 5 alone resulted in the activation of cell wall integrity (CWI) signaling, and deletion mutants were then used to determine that CWI-mediated chitin synthesis was protective against killing. Using flow cytometry, we confirmed that Hst 5+Zn-treated cells had significantly elevated levels of cell-wall chitin, mannan and β-1,3 glucan compared to Hst 5-treated cells. We then tested the activation of host signaling components involved in C. albicans cell-wall recognition. The immunoblot assay of C. albicans-exposed oral epithelial cells showed increased activation of EphA2 and NF-κB but not EGFR. Interestingly, C. albicans treated with Hst 5+Zn induced the global suppression of pro-inflammatory cytokine release from OECs, but an increase in negative regulator IL-10. Hst 5+Zn-treated cells were more adherent but ultimately less invasive to OECs than control cells, thus indicating lowered virulence. Therefore, Hst 5+Zn-treated C. albicans cells are discerned by epithelial monolayers, but are less virulent and promote anti-inflammatory signaling, suggesting that Hst 5+Zn in combination could play a role in regulating commensalism of oral C. albicans through cell wall reorganization.
Highlights
The salivary peptide Histatin 5 (Hst 5) is constitutively expressed in human saliva, has potent candidacidal activity for the opportunistic pathogen Candida albicans, and metal ion-binding ability including copper (Cu), iron (Fe), and zinc (Zn) ions [1,2,3]
We found that 92% of cells treated with Hst 5 survived compared to dilute media buffer (DMB)-only control cells
We investigated the response of 3 major mitogen activated protein kinase (MAPK) signaling pathways (Mkc1, Cek1 and Hog1) in cells treated with Hst 5 or Hst 5∆MB with or without added Zn (Figure 1B)
Summary
The salivary peptide Histatin 5 (Hst 5) is constitutively expressed in human saliva, has potent candidacidal activity for the opportunistic pathogen Candida albicans, and metal ion-binding ability including copper (Cu), iron (Fe), and zinc (Zn) ions [1,2,3]. MAPK stress signaling induces changes in the geometry of cell-wall components β-1,3 glucan and mannan that can lead to altered host cell recognition of C. albicans cells [22,28,29]. Oral epithelial cells (OECs) are the first cell type in the oral environment that encounter C. albicans and are able to discern between the relatively benign yeast form and the more virulent hyphal form [35] Receptors such as TLR2, TLR4, and Dectin-1 that are typically considered major Candida cellwall component receptors in immune cells [22,36] do not elicit an inflammatory response in OECs but can be involved in general cell sensing and signal modulation [37]. These Hst 5+Zn treated cells had elevated host adhesion but were less invasive than cells treated with Hst 5 alone
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