Candidacidal effects of two antimicrobial peptides: histatin 5 causes small membrane defects, but LL-37 causes massive disruption of the cell membrane

Hertog, Alice L. den; Marle, J. van; Veen, Henk A. van; Hof, Wim van’t; Bolscher, Jan G. M.; Veerman, E.C.I.; Amerongen, A. van Nieuw

doi:10.1042/bj20042099

Cited by 157 publications

(123 citation statements)

References 40 publications

(48 reference statements)

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“…Thus, the membrane lytic effects of Hst 5 reported previously may be due to use of higher concentrations of this peptide, although no evidence of a "single" pore as reported in that study (28) has been corroborated. Lack of permanent pores has also been demonstrated previously by immunogold labeling and freeze fracturing of the plasma membrane of Hst 5-treated C. albicans cells (30,31).…”

Section: Cell Membrane: the Misidentified Target Of Hstmentioning

confidence: 66%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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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.

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Section: Cell Membrane: the Misidentified Target Of Hstmentioning

confidence: 66%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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“…In C. albicans, LL-37 initially associates with the cell wall and/or the cytoplasmic membrane (9). Treatment of fungal cells with large amounts of the peptide resulted in a breakdown of the membrane into discrete vesicles and led to rapid efflux of small molecules, such as ATP, as well as larger molecules with molecular masses up to 40 kDa.…”

Section: Activity Of Human Amps Against C Albicansmentioning

confidence: 99%

Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014

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Antimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungus Candida albicans colonizes different host niches as part of the normal human microbiota. Proliferation of C. albicans is regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host, C. albicans has developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms prevent C. albicans from the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack and C. albicans resistance mechanisms and current developments in the use of AMPs as antifungal agents.

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“…Such invaginations, also called furrows or troughs, have since been identified in additional freeze fracture EM studies of S. cerevisiae (2)(3)(4)(5)(6) and other fungi (7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Eisosome Ultrastructure and Evolution in Fungi, Microalgae, and Lichens

et al. 2015

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Eisosomes are among the few remaining eukaryotic cellular differentations that lack a defined function(s). These trough-shaped invaginations of the plasma membrane have largely been studied in Saccharomyces cerevisiae, in which their associated proteins, including two BAR domain proteins, have been identified, and homologues have been found throughout the fungal radiation. Using quick-freeze deep-etch electron microscopy to generate high-resolution replicas of membrane fracture faces without the use of chemical fixation, we report that eisosomes are also present in a subset of red and green microalgae as well as in the cysts of the ciliate Euplotes. Eisosome assembly is closely correlated with both the presence and the nature of cell walls. Microalgal eisosomes vary extensively in topology and internal organization. Unlike fungi, their convex fracture faces can carry lineagespecific arrays of intramembranous particles, and their concave fracture faces usually display fine striations, also seen in fungi, that are pitched at lineage-specific angles and, in some cases, adopt a broad-banded patterning. The conserved genes that encode fungal eisosome-associated proteins are not found in sequenced algal genomes, but we identified genes encoding two algal lineage-specific families of predicted BAR domain proteins, called Green-BAR and Red-BAR, that are candidate eisosome organizers. We propose a model for eisosome formation wherein (i) positively charged recognition patches first establish contact with target membrane regions and (ii) a (partial) unwinding of the coiled-coil conformation of the BAR domains then allows interactions between the hydrophobic faces of their amphipathic helices and the lipid phase of the inner membrane leaflet, generating the striated patterns.

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Candidacidal effects of two antimicrobial peptides: histatin 5 causes small membrane defects, but LL-37 causes massive disruption of the cell membrane

Cited by 157 publications

References 40 publications

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Eisosome Ultrastructure and Evolution in Fungi, Microalgae, and Lichens

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