Fungal pathogens are a worldwide threat to human health. Candida albicans, which is normally a commensal resident of the oral cavity, can cause oropharyngeal candidiasis (OPC) in individuals whose immune system is compromised by AIDS, chemotherapy, or use of immunosuppressant drugs. Histatins (Hsts) are a family of histidine-rich cationic proteins secreted by human major salivary glands that largely contribute to the antifungal activity of saliva. Hst 5 is strongly fungicidal in vitro, however its activity in sliva is substantially attenuated by proteolytic degradation as well as by other unknown factors. We identified C. albicans polyamine Dur transporters to be the conduit by which Hst 5 is translocated intracellularly, and designed an Hst 5 conjugated with the polyamine spermidine (Hst 54-15-Spd) that has superior uptake and killing properties. Hst 54-15-Spd appears to be resistant to salivary proteases and assumes a more unordered structure that may make it a better substrate for C. albicans Dur transporters. The basis for its proteolytic resistance and uptake kinetics will be examined in Aim 1. Various factors affect the outcome of antimicrobial therapy. These include the biological state of the pathogen and the availability of extraneous ligands such as metals outside the cell. C. albicans has three major signaling pathways that allow its adaptation to environmental stresses including Hst 5. We found that phosphorylation of Cek1 (P-Cek1) conditions cells to become more sensitive to Hst 5, a finding we will delineate and exploit as a combinatorial therapeutic in protective and treatment strategies in Aim 2. We found that iron, one of the most abundant metal in saliva, strongly binds Hst 5 and modifies its structure as well as reducing its killing activity. Intracellular Hst 5 may bind fungal cellular laile iron pools and redistribute its reserves, targeting it to the vacuoles and mitochondria, the two sites where Hst 5 accumulates. We propose that iron as well as other salivary metals have an unexplored role in modifying Hst 5 activity both in saliva as well as within the fungal cell that wll be examined in Aim 3

Public Health Relevance

Candidal albicans is a human fungal pathogen that causes oral thrush and can become a serious threat to human health especially in immuno-compromised people. Salivary histatins (Hsts) are natural peptides that rapidly kill C. albicans, but their activity is reduced by degradation in saliva and by salivary iron. The aims of this projet are to identify how to make Hsts more resistant to degradation, and to use a mouse model of thrush to test novel combinations of therapies to enhance Hst activity, and to test how salivary metals including iron affect Hst killing of C. albicans.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lunsford, Dwayne
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State University of New York at Buffalo
Schools of Dentistry/Oral Hygn
United States
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Pathirana, Ruvini U; Friedman, Justin; Norris, Hannah L et al. (2018) Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses. Antimicrob Agents Chemother 62:
McCall, Andrew; Edgerton, Mira (2017) Real-Time Approach to Flow Cell Imaging of Candida albicans Biofilm Development. J Fungi (Basel) 3:
Jephthah, Stephanie; Henriques, João; Cragnell, Carolina et al. (2017) Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study. J Chem Inf Model 57:1330-1341
Kumar, Rohitashw; Breindel, Christine; Saraswat, Darpan et al. (2017) Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition. Sci Rep 7:2908
Du, Han; Puri, Sumant; McCall, Andrew et al. (2017) Human Salivary Protein Histatin 5 Has Potent Bactericidal Activity against ESKAPE Pathogens. Front Cell Infect Microbiol 7:41
Hampe, Irene A I; Friedman, Justin; Edgerton, Mira et al. (2017) An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses. PLoS Pathog 13:e1006655
Saraswat, Darpan; Kumar, Rohitashw; Pande, Tanaya et al. (2016) Signalling mucin Msb2 Regulates adaptation to thermal stress in Candida albicans. Mol Microbiol 100:425-41
Tati, Swetha; Davidow, Peter; McCall, Andrew et al. (2016) Candida glabrata Binding to Candida albicans Hyphae Enables Its Development in Oropharyngeal Candidiasis. PLoS Pathog 12:e1005522
Cullen, Paul J; Edgerton, Mira (2016) Unmasking fungal pathogens by studying MAPK-dependent cell wall regulation in Candida albicans. Virulence 7:502-5
Salvatori, O; Puri, S; Tati, S et al. (2016) Innate Immunity and Saliva in Candida albicans-mediated Oral Diseases. J Dent Res 95:365-71

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