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Antimicrobial Agents and Chemotherapy, September 1999, p. 2256-2262, Vol. 43, No. 9
0066-4804/99/$04.00+0

Histatin 3-Mediated Killing of Candida albicans: Effect of Extracellular Salt Concentration on Binding and Internalization

Yanying Xu,1,dagger Indu Ambudkar,1 Hisako Yamagishi,1,Dagger William Swaim,2 Thomas J. Walsh,3 and Brian C. O'Connell1,*

Gene Therapy and Therapeutics Branch1 and Cellular Imaging Core Facility,2 National Institute of Dental and Craniofacial Research, and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,3 Bethesda, Maryland 20892

Received 8 April 1999/Returned for modification 28 May 1999/Accepted 12 July 1999

Human saliva contains histidine-rich proteins, histatins, which have antifungal activity in vitro. The mechanism by which histatins are able to kill Candida albicans may have clinical significance but is currently unknown. Using radiolabeled histatin 3, we show that the protein binds to C. albicans spheroplasts in a manner that is dependent on time and concentration. Binding to the spheroplasts was saturable and could be competed with unlabeled histatin 3. A single histatin 3 binding site with a Kd = 5.1 µM was detected. Histatin 3 binding resulted in potassium and magnesium efflux, predominantly within the first 30 min of incubation. Studies with fluorescent histatin 3 demonstrate that the protein is internalized by C. albicans and that translocation of histatin inside the cell is closely associated with cell death. Histatin binding, internalization, and cell death are accelerated in low-ionic-strength conditions. Indeed, a low extracellular salt concentration was essential for cell death to occur, even when histatin 3 was already bound to the cell. The interaction of histatin 3 with C. albicans, and subsequent cell death, is inhibited at low temperature. These results demonstrate that the candidacidal activity of histatin 3 is not due exclusively to binding at the cell surface but also involves subsequent interactions with the cell.

* Corresponding author. Mailing address: School of Dental Science, Trinity College, Dublin 2, Ireland. Phone: 353-1-612-7312. Fax: 353-1-612-7298. E-mail: BrianO'Connell{at}dental.tcd.ie.

dagger Present address: School of Stomatology, Beijing Medical University, Haidan District, Beijing 10081, China.

Dagger Present address: Department of Pharmacology, Tokyo Dental College, Mihamaku, Chiba 261-8502, Japan.

Antimicrobial Agents and Chemotherapy, September 1999, p. 2256-2262, Vol. 43, No. 9
0066-4804/99/$04.00+0


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