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: 4.48). 02/2013; 57(4). DOI: 10.1128/AAC.02295-12
Source: PubMed


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, Oct 06, 2015
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    • "(Chengetal.,2012).C.albicansontheotherhandhasevolved severalmechanismstocontrolandevadetheantimicrobial activityoflocalandnewlyattractedphagocyticcellsbyinhibiting recognition,trafficking,andeffectorrelease,thusovercoming severalimportantstresses(Lopez,2013;Luoetal.,2013). Neutrophilsaretheprevalentimmunecelltypeinanti- Candidaimmunity(MoyesandNaglik,2011;Luoetal.,2013). "
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    ABSTRACT: The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.
    Frontiers in Microbiology 06/2015; 6:625. DOI:10.3389/fmicb.2015.00625 · 3.99 Impact Factor
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    • "The C. albicans DHA1 transporter CaFlu1 was found to complement fluconazole hypersusceptibility in a S. cerevisiae Δpdr5 mutant, but not to have a significant role in fluconazole resistance in C. albicans (Calabrese et al., 2000). On the other hand, Flu1 was more recently shown to confer resistance to the salivary human antimicrobial peptide histatin 5, playing a direct role in its efflux from C. albicans cells, thus reducing histatin 5 toxicity (Li et al., 2013). Of a total of 26 DHA transporters found to be encoded by C. albicans genome, 18 are still uncharacterized. "
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    ABSTRACT: Infections caused by opportunistic fungal pathogens have reached concerning numbers due to the increase of the immunocrompromised human population and to the development of antifungal resistance. This resistance is often attributed to the action of multidrug efflux pumps, belonging to the ATP-binding cassette (ABC) superfamily and the major facilitator superfamily (MFS). Although many studies have focused on the role of ABC multidrug efflux transporters, little is still known on the part played by the Drug:H(+) Antiporter (DHA) family of the MFS in this context. This review summarizes current knowledge on the role in antifungal drug resistance, mode of action and phylogenetic relations of DHA transporters, from the model yeast S. cerevisiae to pathogenic yeasts and filamentous fungi. Through the compilation of the predicted DHA transporters in the medically relevant Candida albicans, C. glabrata, C. parapsilosis, C. lusitaniae, C. tropicalis, C. guilliermondii, Cryptococcus neoformans, and Aspergillus fumigatus species, the fact that only 5% of the DHA transporters from these organisms have been characterized so far is evidenced. The role of these transporters in antifungal drug resistance and in pathogen-host interaction is described and their clinical relevance discussed. Given the knowledge gathered for these few DHA transporters, the need to carry out a systematic characterization of the DHA multidrug efflux pumps in fungal pathogens, with emphasis on their clinical relevance, is highlighted.
    Frontiers in Physiology 05/2014; 5:197. DOI:10.3389/fphys.2014.00197 · 3.53 Impact Factor
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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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    ABSTRACT: Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed.
    Frontiers in Microbiology 03/2014; 5:97. DOI:10.3389/fmicb.2014.00097 · 3.99 Impact Factor
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