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Infection and Immunity, December 2000, p. 6848-6856, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Released ATP Is an Extracellular Cytotoxic Mediator in Salivary Histatin 5-Induced Killing of Candida albicans

Svetlana E. Koshlukova,1 Marcelo W. B. Araujo,1 Didi Baev,1 and Mira Edgerton1,2,*

Departments of Oral Biology1 and Restorative Dentistry,2 School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York 14214

Received 19 May 2000/Returned for modification 11 August 2000/Accepted 7 September 2000

Salivary histatins (Hsts) are antifungal peptides with promise as therapeutic agents against candidiasis. Hst 5 kills the fungal pathogen Candida albicans via a mechanism that involves release of cellular ATP in the absence of cytolysis. Here we demonstrate that released ATP has a further role in Hst 5 killing. Incubation of the cells with ATP analogues induced cell death, and addition of the ATP scavenger apyrase to remove extracellular ATP released during Hst 5 treatment resulted in a reduction in cell killing. Experiments using anaerobically grown C. albicans with decreased susceptibility to Hst 5 confirmed that depletion of cellular ATP as a result of ATP efflux was not sufficient to cause cell death. In contrast to Hst-susceptible aerobic cultures, anaerobically grown cells were not killed by exogenously applied ATP. These findings established that Hst binding, subsequent entry into the cells, and ATP release precede the signal for cytotoxicity, which is mediated by extracellular ATP. In a higher-eukaryote paradigm, released ATP acts as a cytotoxic mediator by binding to membrane nucleotide P2X receptors. Based on a pharmacological profile and detection of a C. albicans 60-kDa membrane protein immunoreactive with antibody to P2X7 receptor, we propose that released ATP in response to Hst 5 activates candidal P2X7-like receptors to cause cell death.

* Corresponding author. Mailing address: 310 Foster Hall, SUNY at Buffalo Main Street Campus, 3435 Main St., Buffalo, NY 14214. Phone: (716) 829-3067. Fax: (716) 829-3942. E-mail: edgerto{at}buffalo.edu.

Infection and Immunity, December 2000, p. 6848-6856, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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