School of Dental Medicine - University at Buffalo

Edgerton, Mira D.D.S., Ph.D. Research Professor, Department of Oral Biology; Research Professor, Department of Restorative Dentistry

Address:

310 Foster Hall

Buffalo, NY 14214

(716)829-3067

edgerto@buffalo.edu

Faculty Profile

EDUCATION
SUNY Buffalo, Oral Biology Ph.D. 1994 Oral Biology
SUNY Buffalo, School of Dental Medicine M.S. 1984 Oral Sciences
Roswell Park Memorial Institute Cert. Spec. 1982 Maxillofacial Pros.
SUNY Buffalo, School of Dental Medicine Cert. Spec. 1981 Prosthodontics
CWRU, Dental School, Cleveland, Ohio D.D.S. 1979 Dentistry
Ohio State Univiversity, Columbus, Ohio B. S. 1975 Biochemistry

Research Profile

EDGERTON LAB
Oropharyngeal candidiasis (OPC), caused by Candida albicans, is a frequent opportunistic disease in patients receiving cancer chemotherapy, AIDS patients, diabetics, and in many elderly groups especially those using oral prostheses. Alteration of the quantity and quality of saliva, especially reduction in antifungal peptides or changes in levels of human ß-defensins (hBDs), are underlying factors in development of oral candidiasis (picture).



AIDS patients, who lack CD4+ T cells are highly susceptible to OPC, indicating that these cells are critically important for immunity to Candida in the oral mucosa. Although immunity to OPC has long been thought to involve Th1 cells, mice lacking the Th1 signature cytokine IFN? are resistant to this disease. We recently reported (Conti et al., 2009), that the newly described Th17 subset of T cells is absolutely required for effective host defense against OPC. Mice deficient in Th17 cells or in the receptor for IL-17 develop fungal lesions on the tongue, palate and buccal mucosa following exposure to Candida that resembles the human clinical appearance of OPC.



The Edgerton lab and Gaffen lab (University of Pittsburgh) are collaborating to explore whether administration of anti-microbial factors can be used as an effective treatment of OPC, and to develop a mouse model by which T cell responses can be visualized and tracked during infection.

Histatins are a family of histidine-rich cationic proteins secreted by the major salivary glands in humans and higher primates that significantly contribute to the antifungal activity of saliva (hst 5 pred struct pict). Histatin 5 (Hst 5) is strongly fungicidal by causing selective loss of intracellular ions and ATP from C. albicans. Bleeding of cellular ions results in reduction of cell volume which is a hallmark of osmotically-induced cell death. HBDs share some similarities in fungicidal pathways with Hst 5, but their precise mechanism of toxicity is not known.

The research areas of the Edgerton lab are to define key elements required for Hst 5 and hBD toxicity focused on fungal cell uptake and adaptive responses. This approach may lead to alternative peptide-based therapies for treatment of oral candidiasis, which is currently limited to a small group of antifungal drugs. Ongoing projects in the Edgerton lab are to:

1. Identify transport mechanisms by which Hst 5 and hBD enter C. albicans cells. Cytotoxicity of Hst 5 is initiated upon reaching the cytosolic of C. albicans. Intracellular peptide transport is the rate limiting step for fungicidal activity, therefore defining the molecular identity of the transport mechanism is crucial.



We have identified and mapped Hst 5-binding sites of Candidal Ssa2 proteins that are necessary chaperone proteins for localization and intracelluar transport of Hst 5 into target yeast cells. A major objective of our lab is to identify central transport mechanisms of Hst 5 and other antimicrobial proteins.







2. Determine critical binding and uptake elements for cationic peptides. We have found that disruption of initial binding of Hst 5 to the yeast cell wall surface by extracelluar salts prevents fungicidal activity, and is therefore a significant barrier to use of Hst 5 or other related cationic peptides as antifungal drugs.



Thus, design of salt-insenstive peptides which are efficiently transported into the cell is essential in order to develop peptide-based therapeutic agents for candidiasis. Our lab investigates critical amino acids motifs required for Hst 5 activity as well as other antimicrobial peptides.

3. Identify Candidal stress response mechanisms involved in resistance to cationic peptides. We have identified the C. albicans Hog1 MAPKinase pathway to be an important response mechanism for recovery of cells from osmotic stress induced by Hst 5. Candidal cells in the oral environment exposed to low physiological levels of antifungal peptides may develop resistance through constitutive activation of Hog1p. Therefore, understanding these response pathways and their initiating sensors will guide therapies to overcome Candidal adaptive resistance. Our lab focuses on understanding the cellular mechanisms of C. albicans membrane sensors Sho1 and Sln1 in mediating stress response induced by Hst 5 through activation of Hog1 MAP Kinase pathways.




Our Lab Personnel

Representative Publications Search Publications in MEDLINE

Sun, J. N., Li, W., Jang, W. S., Nayaar, N., Sutton, M. and M. Edgerton. 2008. Uptake of the Antifungal Cationic Peptide Histatin 5 by C. albicans Ssa2p Requires Binding with Non-Conventional Sites within the ATPase Domain. Molec. Microbiol. 70:1246–1260

Conti, H. R., Shen, F., Nayyar, N., Lindemann, M. J., Ho, A. W., Stocum, E. Yu, J. J., Jung, J. W., Filler, S. G., Masso-Welch, P., Edgerton, M. and S. L. Gaffen. 2009. Th17/IL-17 receptor signaling and not Th1 cells are essential for host defense against oral candidiasis. J. Exp. Med. 206:299-311

C. R. Pusateri, E. A. Monaco, and M. Edgerton. 2009. Sensitivity of Candida Albicans Biofilm Cells Grown on Denture Acrylic to Antifungal Proteins and Chlorhexidine. Arch. Oral Biol. epub Feb.

Sun, J. N., Nayyar, N., Solis, N., Li, W., Dongari-Bagtzoglou, A., Filler, S. G., and M. Edgerton. 2009. Ssa1 proteins are virulence determinants in Candida albicans
 that affect adhesion and tissue invasion. In preparation for Molec. Cell.

Jang, W. S., Li, X. S., Sun, J. N., and M. Edgerton. 2008. The P-113 fragment of Histatin 5 requires a specific peptide sequence for intracellular translocation in Candida albicans, which is independent of cell wall binding. Antimicrob. Agents Chemother. 52: 497-504 (Epub 2007 Nov12)

Vylkova, S., Jang, W. S., Li, W., Nayyar, N., and M. Edgerton. 2007. Histatin 5 initiates osmotic stress response in Candida albicans via activation of the HOG MAP kinase pathway. Eukaryot. Cell. 6: 1876-1888

Vylkova, S., Sun, J. N., and M. Edgerton. 2007. The role of released ATP in killing Candida albicans and other extracellular microbial pathogens by cationic peptides. Purinergic Signalling 3:91-97.

Vylkova, S., Nayyar, N., Li, W. and M. Edgerton. 2007. Human beta-defensins kill Candida albicans in an energy-dependent and salt-sensitive manner without causing membrane disruption. Antimicrob. Agents Chemother. 51:154-161 (Epub 2006, Oct 30)

Li, X. S., Sun, J. N., Okamoto-Shibayama, K., and M. Edgerton. 2006. Candida albicans cell wall Ssa proteins bind and facilitate import of salivary Histatin 5 required for toxicity. J. Biol. Chem. 281:22453-22463 (Epub, May 23)

Vylkova, S., Li, X. S., Berner, J. C., and M. Edgerton. 2006. Distinct antifungal mechanisms: beta-defensins require Candida albicans Ssa1 protein, while Trk1p mediates activity of cysteine-free cationic peptides. Antimicrob. Agents Chemother. 50:324-331.

Baev, D., Rivetta, A., Vylkova, S., Sun, J. N., Zeng, G.-F., Slayman, C. L. and M. Edgerton. 2004. TRK1 potassium transporter is the critical effector for killing of Candida albicans by the cationic protein, Histatin 5. J. Biol. Chem. 279:55060-55072. (Epub, Oct 13)

Wunder, D., Dong, J. Vylkova, S., and Error! Contact not defined., M. 2004. Salivary Histatin 5 candidacidal activity does not induce programmed cell death markers. Antimicrob. Agents Chemother. 48:110-115.

Li, X. S., Reddy, M. S., Baev, D. and Edgerton, M. 2003. Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. J. Biol. Chem. 278:28553-28561.

Baev, D., Rivetta, A., Li, X. S., Vylkova, S., Bashi, E., Slayman, C. L. and Edgerton, M. 2003. Killing of Candida albicans by human salivary Histatin 5 is modulated, but not determined, by the potassium channel TOK1. Infect. Immun. 71:3251-3260.

Dong, J. Vylkova, S., Li, X.S., and Edgerton, M. 2003. Calcium blocks fungicidal activity of human salivary Histatin 5 through disruption of binding with Candida albicans J. Dent. Res. 82:748-752.

Baev, D., Li, X., Dong, J., Keng, P. and M. Edgerton. 2002. Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Infect. Immun. 70:4777-4784.

Baev, D., Li, X., and M. Edgerton. 2001. Genetically engineered human salivary histatin genes are functional in Candida albicans: development of a new system for studying histatin candidacidal activity. Microbiol. 147:323:3334.

Edgerton, M. and S. E. Koshlukova. 2000. Salivary non-immune antimicrobial proteins. Advances Dent. Res. 14:16-21

Edgerton, M., Koshlukova, S. E., Araujo, M. W. B., Patel, R. C., Dong J. and J. A. Bruenn. 2000. Salivary histatin 5 and human neutrophil defensin 1 kill Candida albicans via shared pathways. Antimicrob. Agents Chemother. 44:3310-3316

Koshlukova, S. E., Araujo, M.W.B., Baev, D. and Edgerton, M. 2000. Released ATP is an extracellular cytotoxic mediator in salivary histatin 5-induced killing of Candida albicans. Infect. Immun. 68:6848-6856.

Koshlukova, S. E., Lloyd, T. L., Araujo, M.W. B., and M. Edgerton. 1999. Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J. Biol. Chem. 274: 18872-18879

Edgerton, M., Koshlukova, S. E., Lo, T. E., Chrzan, B. G., Straubinger, R. M. and P.A. Raj. 1998. Candidacidal activity of salivary Histatins: Identification of a Histatin 5 binding protein on Candida albicans. J. Biol. Chem. 273:20438-2044

PUBLISHED ABSTRACTS (recent selected out of 56)
Nayyar, N., W. Li, S. G. Filler, N. Solis, A. Dongari-Bagtzoglou, and M. Edgerton. 2008. Ssa1 proteins play an important role in cell adhesion and virulence of Candida albicans. 9th ASM Conference on Candida and Candidiasis.

Sun, J.N., W. Li, N. Nayyar, W.S. Jang and M. Edgerton. 2008. Epitopes within the ATPase domain of C. albicans Ssa2p are required for binding and uptake of the antifungal peptide Histatin 5. 9th ASM Conference on Candida and Candidiasis.

Li, X.S., J.N. Sun, and M. Edgerton. 2007. Lysine Residues are Required for Histatin Translocation into Candida albicans. J. Dental Res. 86: Spec. Issue A, 2251

Sun, J.N., X.S. Li, and M. Edgerton. 2007. ATP hydrolysis mediates C. albicans ssa2p-Histatin5 complex formation
. J. Dental Res. 86: Spec. Issue A, 1430.

Nayaar, N., S. Filler, N. Solis, J.N. Sun, and M. Edgerton. 2007. Ssa1 proteins are important virulence determinants in Candida albicans
. J. Dental Res. 86: Spec. Issue A, 1203

Okamoto-Shibayama, K., S. Vylkova, and M. Edgerton. 2007. Microarray analyses of Candida albicans transporter gene expression with Hst 5. J. Dental Res. 86: Spec. Issue A, 1797

Vylkova, S., Sun, J. N., and M. Edgerton. 2006. Human beta defensins and histatin 5 have overlapping mechanisms of killing of Candida albicans. ASM 160th General Meeting. F-004.

Sun, J. N., Li, X. S., and M. Edgerton. 2006. Candida albicans cell wall HSP70 proteins mediate binding with the cationic peptide Histatin 5. A166. 8th ASM Conference on Candida and Candidiasis.

Vylkova, S., Nayyar, N. and M. Edgerton. 2006. Human beta defensins kill Candida albicans in a salt-sensitive and energy-dependent manner that does not involve membrane disruption. C138. 8th ASM Conference on Candida and Candidiasis.