Salivary Histatin 5 and Human Neutrophil Defensin 1 Kill
            <i>Candida albicans</i>
            via Shared Pathways

Edgerton, Mira; Koshlukova, Svetlana E.; Araujo, Marcelo W B; Patel, Rashmi C.; Dong, Jin; Bruenn, Jeremy A.

doi:10.1128/aac.44.12.3310-3316.2000

Cited by 102 publications

(95 citation statements)

References 43 publications

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“…Our respiratory measurements contrast with previous publications by Edgerton and coworkers, who reported that histatin 5 had virtually no effect on yeast cellular respiration (15,22). Surprisingly, data generated by this group suggested that cells exposed to histatin were dead and had released all of their ATP, but continued to respire for 1.5 h. Although these observations remain unexplained, the results reported here show that there is an almost perfect correlation between inhibition of respiration and cell killing when either logarithmic-phase or stationary-phase cells were used.…”

Section: Discussioncontrasting

confidence: 56%

The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species

Helmerhorst

Troxler

Oppenheim

2001

Proc. Natl. Acad. Sci. U.S.A.

207

157

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Previous studies have shown that the human salivary antifungal peptide histatin 5 is taken up by Candida albicans cells and associates intracellularly with mitochondria. The purpose of the present study was to investigate the biological consequence of this specific subcellular targeting. Histatin 5 inhibited respiration of isolated C. albicans mitochondria as well as the respiration of intact blastoconidia in a dose and time-dependent manner. A nearly perfect correlation was observed between histatin-induced inhibition of respiration and cell killing with either logarithmic-or stationary-phase cells, but stationary-phase cells were less sensitive. Because nonrespiring yeast cells are insensitive to histatin 5, the potential mechanistic relationship between histatin 5 interference with the respiratory apparatus and cell killing was explored by using an oxygen radical sensitive probe (dihydroethidium). Fluorimetric measurements showed that histatin 5 induced the formation of reactive oxygen species (ROS) in C. albicans cells as well as in isolated mitochondria and that ROS levels were highly correlated with cell death. In the presence of an oxygen scavenger (L-cysteine), cell killing and ROS formation were prevented. In addition, the membrane-permeant superoxide dismutase mimetic 2,2,6,6-tetramethylpiperidine-N-oxyl, abolished histatin-induced ROS formation in isolated mitochondria. In contrast to histatin 5, the conventional inhibitors of the respiratory chain, sodium cyanide or sodium azide, neither induced ROS nor killed yeast cells. These data provide strong evidence for a comprehensive mechanistic model of histatin-5-provoked yeast cell death in which oxygen radical formation is the ultimate and essential step.

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Section: Discussioncontrasting

confidence: 56%

The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species

Helmerhorst

Troxler

Oppenheim

2001

Proc. Natl. Acad. Sci. U.S.A.

207

157

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“…These peptides can be expressed either constitutively or induced in response to pathogen-associated molecular patterns, such as bacterial LPS, or inflammatory mediators, such as IL-6 and TNF-␣ (1,2). Although some of these peptides have the ability to kill microorganisms (3,4), leading to their categorization as antimicrobial peptides, they also appear to have functions in modulating immune responses (5)(6)(7). The role of cationic peptides has been considered of primary significance to the innate immune response.…”

mentioning

confidence: 99%

“…The only receptor described for LL-37 to date is formyl peptidelike receptor 1 (FPRL-1), 3 a pertussis toxin-sensitive, G proteincoupled receptor that has been proposed to be the chemotactic receptor on monocytes, neutrophils, and subsets of T cells (12). The recently demonstrated ability of LL-37 to induce mast cell chemotaxis is also pertussis toxin sensitive and thus mediated by a G protein-coupled receptor; however, the FPRL-1 receptor was not found to be involved (20).…”

mentioning

confidence: 99%

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

Bowdish

Davidson

Speert

et al. 2004

The Journal of Immunology

220

229

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LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.

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“…The fungicidal action of histatins requires active mitochondria (Helmerhorst et al, 1999a). α-defensins and histatins share some aspects of their antifungal action which is associated with ATP transport and reaction with purinergic-like cell surface receptors (Edgerton et al, 2000). The relationship of histatins and α-and β-defensins with oral Candida is not clear, but these peptides may work synergistically.…”

Section: Histatinsmentioning

confidence: 99%

Antimicrobial Peptides in the Oral Environment: Expression and Function in Health and Disease

2005

Current Issues in Molecular Biology

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The oral cavity is a unique environment in which antimicrobial peptides play a key role in maintaining health and may have future therapeutic applications. Present evidence suggests that α-defensins, β-defensins, LL-37, histatin, and other antimicrobial peptides and proteins have distinct but overlapping roles in maintaining oral health and preventing bacterial, fungal, and viral adherence and infection. The expression of the inducible hBD-2 in normal oral epithelium, in contrast to other epithelia, and the apparent differential signaling in response to commensal and pathogenic organisms, provides new insights into innate immunity in this body site. Commensal bacteria are excellent inducers of hBD-2 in oral epithelial cells, suggesting that the commensal bacterial community acts in a manner to benefit the overall innate immune readiness of oral epithelia. This may have major significance for understanding host defense in the complex oral environment. The oral environmentThe oral cavity is a unique environment. Oral mucosa is a critical protective interface between external and internal environments and must serve as a barrier to the myriad microbial species present in this warm, moist environment. The oral cavity is the only area of the body in which hard tissues break through the epithelial surface. The periodontal epithelium surrounding the tooth is specialized to form an attachment and seal around each tooth. This unique function imparts special challenges to the tissue and leads to certain vulnerabilities associated with periodontal disease, especially in view of the continual exposure to the bacterial biofilm (dental plaque) that forms on the tooth surface at the junction of the soft tissue. Thus, this anatomical region is one where there is a significant risk of bacterially induced infection and inflammation.Antimicrobial peptides are important contributors to maintaining the balance between health and disease in this complex environment. These include several salivary antimicrobial peptides, the β-defensins expressed in the epithelium, the α-defensins expressed in neutrophils, and the cathelicidin, LL-37, expressed in both epithelium and neutrophils. These peptides are part of the host innate immune response in this environment. Epithelia, polymorphonuclear leukocytes (neutrophils), and saliva all contribute to the maintaining the health of the oral cavity in overlapping but independent ways. This review will focus on the human oral cavity and include 1) the expression and function of antimicrobial peptides in the oral cavity in the context of innate immune responses, 2) regulation of β-defensins which has led to advances in our understanding of oral epithelial innate immunity, and 3) functional efficacy against oral microbes when it is known. Epithelial antimicrobial peptidesHistorically, the oral epithelium has been considered mainly as a passive covering that becomes damaged and ulcerated in disease. This view has changed dramatically and the epithelial compartment is now seen as providing both...

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Salivary Histatin 5 and Human Neutrophil Defensin 1 Kill Candida albicans via Shared Pathways

Cited by 102 publications

References 43 publications

The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species

The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

Antimicrobial Peptides in the Oral Environment: Expression and Function in Health and Disease

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