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

Puri, Sumant; Edgerton, Mira

doi:10.1128/ec.00095-14

Cited by 153 publications

(165 citation statements)

References 77 publications

(76 reference statements)

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“…Hst 5 downregulates specific mitochondrial proteins involved in C. albicans energy metabolism and upregulates biosynthetic proteins (14), which ultimately leads to a drastic decrease in mitochondrial ATP synthesis. The role of the candidacidal mechanism of Hst 5 is also discussed in detail in the accompanying minireview by Puri and Edgerton (20).…”

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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Section: Activity Of Human Amps Against C Albicansmentioning

confidence: 99%

Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014

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“…Histatin 5 is a potent antifungal peptide acting upon multiple intracellular components to induce oxidative stress and mitochondrial malfunction in Candida albicans (110). However, its direct antibacterial activity has only been described for Streptococcus mutans (111), one of the major oral bacteria implicated in dental caries (112).…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Intracellular Targeting Mechanisms by Antimicrobial Peptides

Fang

Sekaran

2017

Antimicrob Agents Chemother

406

366

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Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.

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“…After 1 h of incubation, cells were harvested at 2,500 ϫ g and 4°C for 2 min and washed with 10 mM pH 7.4 sodium phosphate buffer (NaPB). For protein extraction, cell pellets were placed on ice and resuspended in 300 ml 10% TCA buffer (10 mM Tris HCl [pH 8.0], 10% trichloroacetic acid, 25 mM NH 4 OAc, 1 mM sodium EDTA). Total cellular lysate was isolated by disrupting cells with acid-washed beads by vortexing for 1 min for 10 cycles using a FastPrepH-24 Instrument (MP Biomedicals LLC).…”

Section: Strains and Chemicalsmentioning

confidence: 99%

“…Hst 5 initially binds to the C. albicans cell wall followed by active translocation into the cytosol by Dur3 and Dur31 polyamine transporters (3). Although Hst 5 appears to have several intracellular targets (4), it ultimately induces selective leakage of small intracellular ions and nucleotides, causing gradual cell death (4).…”

mentioning

confidence: 99%

Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

Puri

Tati

et al. 2015

Antimicrob Agents Chemother

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Candida albicans is a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC. C. albicans senses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either by N-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility of C. albicans cells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility in C. albicans. Candida albicans is the major etiological organism of oral candidiasis (thrush) in individuals whose immune system is impaired. Naturally occurring antimicrobial peptides, such as defensins and histatins, are promising candidates for the treatment of fungal infections because of their distinct mechanism of action from conventional azole and polyene-based antifungal drugs (1). Salivary histatin 5 (Hst 5) is a fungicidal histidine-rich protein constitutively produced by human salivary gland cells, with physiological concentrations in saliva ranging from 10 to 30 M (2). Hst 5 initially binds to the C. albicans cell wall followed by active translocation into the cytosol by Dur3 and Dur31 polyamine transporters (3). Although Hst 5 appears to have several intracellular targets (4), it ultimately induces selective leakage of small intracellular ions and nucleotides, causing gradual cell death (4).The oral cavity is a challenging environment for fungal colonization due to wide fluctuations in temperature, tonicity, and osmolarity. C. albicans senses environmental changes through its membrane sensors that elicit responses through various signaling pathways, one of the most important being mitogen-activated protein kinase (MAPK) signal transduction pathways (5). Four MAPK pathways have been identified in C. albicans: the highosmolarity glycerol (HOG) pathway, the cell wall integrity Mkc1 pathway, and the Cek1 and Cek2 pathways. The HOG MAPK network is involved in adaptation to both osmotic and oxidative stresses (6-11), as well as heavy metal stresses (11). We found that Hst 5 treatment of C. albicans cells induced rapid activation of the Hog1 pathway (12), related to Hst 5 induction of cellular osmotic stress. C. albicans cells that were first subjected to osmotic stress, to induce Hog1 phosphorylation, became resistant to Hs...

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

Cited by 153 publications

References 77 publications

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Intracellular Targeting Mechanisms by Antimicrobial Peptides

Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

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