A Novel Role for Histatin 5 in Combination with Zinc to Promote Commensalism in C. albicans Survivor Cells

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.

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Candida albicans Cell Wall Glycosylation May Be Indirectly Required for Activation of Epithelial Cell Proinflammatory Responses

Infection and Immunity ◽

10.1128/iai.05591-11 ◽

2011 ◽

Vol 79 (12) ◽

pp. 4902-4911 ◽

Cited By ~ 34

Author(s):

Celia Murciano ◽

David L. Moyes ◽

Manohursingh Runglall ◽

Ayesha Islam ◽

Celine Mille ◽

...

Keyword(s):

Cell Wall ◽

Epithelial Cells ◽

Proinflammatory Cytokine ◽

Cytokine Production ◽

Cell Damage ◽

Proinflammatory Cytokine Production ◽

Content Type ◽

Oral Epithelial Cells ◽

Hypha Formation ◽

Oral Epithelial

ABSTRACTOral epithelial cells discriminate between the yeast and hyphal forms ofCandida albicansvia the mitogen-activated protein kinase (MAPK) signaling pathway. This occurs through phosphorylation of the MAPK phosphatase MKP1 and activation of the c-Fos transcription factor by the hyphal form. Given that fungal cell wall polysaccharides are critical in host recognition and immune activation in myeloid cells, we sought to determine whether β-glucan andN- orO-glycosylation was important in activating the MAPK/MKP1/c-Fos hypha-mediated response mechanism and proinflammatory cytokines in oral epithelial cells. Using a series of β-glucan andN- andO-mannan mutants, we found thatN-mannosylation (via Δoch1and Δpmr1mutants) andO-mannosylation (via Δpmt1and Δmnt1Δmnt2mutants), but not phosphomannan (via a Δmnn4mutant) or β-1,2 mannosylation (via Δbmt1to Δbmt6mutants), were required for MKP1/c-Fos activation, proinflammatory cytokine production, and cell damage induction. However, theN- andO-mannan mutants showed reduced adhesion or lack of initial hypha formation at 2 h, resulting in little MKP1/c-Fos activation, or restricted hypha formation/pseudohyphal formation at 24 h, resulting in minimal proinflammatory cytokine production and cell damage. Further, the α-1,6-mannose backbone of theN-linked outer chain (corresponding to a Δmnn9mutant) may be required for epithelial adhesion, while the α-1,2-mannose component of phospholipomannan (corresponding to a Δmit1mutant) may contribute to epithelial cell damage. β-Glucan appeared to play no role in adhesion, epithelial activation, or cell damage. In summary,N- andO-mannosylation defects affect the ability ofC. albicansto induce proinflammatory cytokines and damage in oral epithelial cells, but this may be due to indirect effects on fungal pathogenicity rather than mannose residues being direct activators of the MAPK/MKP1/c-Fos hypha-mediated immune response.

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Faculty Opinions recommendation of From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11552956.12602054 ◽

2011 ◽

Author(s):

Judith Berman ◽

Anja Forche

Keyword(s):

Candida Albicans ◽

Epithelial Cells ◽

Oral Epithelial Cells ◽

Oral Epithelial

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Assessment of the Effect of Complete Denture Adhesives on Oral Epithelial Cells’ DNA in Elderly Patients with Controlled Diabetes

Egyptian Dental Journal ◽

10.21608/edj.2018.77272 ◽

2018 ◽

Vol 64 (3) ◽

pp. 2747-2756

Author(s):

Noha El-Shaheed ◽

Amira Gomaa ◽

Ashraf Zakaria

Keyword(s):

Epithelial Cells ◽

Elderly Patients ◽

Complete Denture ◽

Oral Epithelial Cells ◽

Denture Adhesives ◽

Oral Epithelial

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Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

Infection and Immunity ◽

10.1128/iai.00282-15 ◽

2015 ◽

Vol 83 (7) ◽

pp. 2614-2626 ◽

Cited By ~ 35

Author(s):

Rohitashw Kumar ◽

Darpan Saraswat ◽

Swetha Tati ◽

Mira Edgerton

Keyword(s):

Candida Albicans ◽

Epithelial Cells ◽

Oral Candidiasis ◽

Oral Microbiome ◽

Proteinase Activity ◽

Adhesion Properties ◽

Content Type ◽

Oral Epithelial Cells ◽

Oral Epithelial ◽

Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

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