title: How does it kill?: understanding the candidacidal mechanism of salivary histatin 5.
abstract: Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA.
authors.forename: Sumant
authors.initials: S
authors.lastname: Puri
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA edgerto@buffalo.edu.
authors.forename: Mira
authors.initials: M
authors.lastname: Edgerton
mesh_terms: D000595:Amino Acid Sequence; D002176:Candida albicans / Q000502:physiology*; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology; D002463:Cell Membrane Permeability; D054808:Histatins / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System; D050296:Microbial Viability; D008969:Molecular Sequence Data; D011485:Protein Binding; D012463:Saliva / Q000378:metabolism
chemical_list: C068075:HTN3 protein, human; D054808:Histatins