Candida albicans Flu1-Mediated Efflux of Salivary Histatin 5 Reduces Its Cytosolic Concentration and Fungicidal Activity

From the Department of Oral Biology University at Buffalo, Buffalo, New York 14214.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 02/2013; 57(4). DOI: 10.1128/AAC.02295-12
Source: PubMed

ABSTRACT Histatin 5 is a salivary human antimicrobial peptide that is toxic to the opportunistic yeast Candida albicans. Fungicial activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to disrupt cellular processes. Previously we observed that total cytosolic levels of Hst 5 were gradually reduced from intact cells, suggesting that C. albicans possesses a transport mechanism for efflux of Hst 5. Since we identified C. albicans polyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be involved in the efflux of Hst 5. C. albicans FLU1 and TPO2 were found to be the closest homologs of S. cerevisiae TPO1 that encodes a major spermidine efflux transporter, indicating the products of these two genes may be involved in efflux of Hst 5. We found flu1Δ/Δ cells, but not tpo2Δ/Δ cells, had significant reduction in their rate of Hst 5 efflux, and had significantly higher cytoplasmic Hst 5 and Hst 5 susceptibility compared to wild type. We also found that flu1Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels of FLU1 were not altered over the course of treatment with Hst 5; therefore Hst 5 is not likely to induce FLU1 gene over-expression as a potential mechanism of resistance. Thus Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible for reduction of its toxicity in C. albicans.

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Available from: Sumant Puri, Jul 09, 2015
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    • "These patients, who have lower levels of this isoenzyme in the saliva, have an increased incidence of oral candidiasis (Meiller et al., 2009; Khan et al., 2013). Also regarding histatin-5, a transport mechanism of efflux mediated by the flu-1 transporter has been described for C. albicans, rendering the pathogen the ability to reduce the isoenzyme cytosolic concentration and fungicidal activity (Li et al., 2013). The LL-37 cathelicidin and histatins bind to cell wall carbohydrates , preventing adhesion of C. albicans to host cells; thus, the release of AMP-binding proteins acts as a decoy for these AMPs, diverting them from binding to fungal cell surface (den Hertog et al., 2005, 2006; Mochon and Liu, 2008). "
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    • "Recently, it was discovered that the efflux pump encoded by FLU1 is also responsible for efflux of the salivary human antimicrobial peptide histatin 5 (Hst5) that is toxic to C. albicans. Li et al. (2013) showed that flu1D/D had significantly reduced efflux rates of Hst5 and significantly higher cytosolic Hst5 concentrations. Moreover, this mutant showed reduced biofilm formation capacity in the presence of Hst5. "
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