Salivary histatins: Structure, function, and mechanisms of antifungal activity

Immunohistochemical studies identified serous cells of the glandular acini as the cells responsible for production of salivary histatins. Histatins exhibit fungicidal activity against several Candida species, Aspergillus fumigatus, some strains of Saccharomyces cerevisiae, and Cryptococcus neoformans. Studies of levels of salivary histatins in vivo show large intersubject variation in both the concentrations of histatins and their rates of degradation. The total concentration of histatins in whole saliva is balanced between secretion of new proteins and removal of "older" proteins by degradation. Endocytosis was initially suggested as a means of histatin cellular entry based upon the observation that bafilomycin, an inhibitor of endosomal acidification, significantly decreased antifungal activity. Confocal imaging of C. albicans cells showed that some histatin 5 was localized to the vacuole but that cells containing only vacuolar histatin were viable. The cell wall of C. albicans is a thick multilayered structure of glucans, chitin, and mannoproteins that protects cells from osmotic stress and maintains structural integrity. Animal and human clinical studies to evaluate histatins as topical agents in prevention of gingivitis reported therapeutic efficacy without adverse side effects. The major requirements for effective use of salt-insensitive fungicidal peptides are selective and specific binding and uptake by candidal cells, efficacy at low concentrations that allow rapid eradication of yeast pathogens within the ionic strength of saliva, and minimal fungal resistance.