Epithelial Antimicrobial Peptides: Review and Significance for Oral Applications

Weinberg, Aaron; Krisanaprakornkit, Suttichai; Dale, Beverly A.

doi:10.1177/10454411980090040201

Cited by 225 publications

(215 citation statements)

References 79 publications

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“…Skin and epithelial tissues are exposed continuously to a variety of microorganisms and thus provide the first line of defense between the host and the environment (53,54). Disruption of this barrier commonly leads to microbial invasion and subsequent inflammation and infection.…”

Section: Discussionmentioning

confidence: 99%

Cloning and Characterization of the Gene for a New Epithelial β-Defensin

Zhang

Hiraiwa

Yasue

et al. 1999

Journal of Biological Chemistry

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Mammalian ␤-defensins are endogenous cysteine-rich peptide antibiotics that are produced either by epithelial cells lining the respiratory, digestive, and urogenital tracts or by granulocytes and macrophages. A growing body of evidence has implicated these peptides in host defense, particularly mucosal innate immunity. We previously reported the cloning of the full-length cDNA for a porcine ␤-defensin (pBD-1), which was found to be expressed throughout the airway and oral mucosa. Here, we provide the structural organization of the pBD-1 gene, showing that the entire gene spans ϳ1.9 kilobases with two short exons separated by a 1.5-kilobase intron. Fluorescence in situ hybridization mapped the pBD-1 gene to porcine chromosome 15q14-q15.1 within a region of conserved synteny to the chromosomal locations of human and mouse ␣-and ␤-defensins. We also provide several independent lines of evidence showing that the pBD-1 gene is expressed constitutively during inflammation and infection, despite its resemblance to many inducible epithelial ␤-defensins in amino acid sequence, genomic structure, and sites of expression. First, stimulation of primary porcine tongue epithelial cells with lipopolysaccharide, tumor necrosis factor-␣, and interleukin (IL)-1␤ failed to up-regulate the expression of pBD-1 mRNA. Second, pBD-1 gene expression was not enhanced in either digestive or respiratory mucosa of pigs following a 2-day infection with Salmonella typhimurium or Actinobacillus pleuropneumoniae. Last, direct transfection of the pBD-1 gene promoter into NIH/3T3 cells showed no difference in reporter gene activity in response to stimulation by lipopolysaccharide and IL-1␤. The constitutive expression of pBD-1 in airway and oral mucosa, which is consistent with a lack of consensus binding sites for nuclear factor-B or NF-IL-6 in its promoter region, suggests that it may play a surveillance role in maintaining the steady state of microflora on mucosal surfaces.

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Section: Discussionmentioning

confidence: 99%

Cloning and Characterization of the Gene for a New Epithelial β-Defensin

Zhang

Hiraiwa

Yasue

et al. 1999

Journal of Biological Chemistry

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“…The more recently isolated -defensins are more basic and longer (34-42 residues), and are expressed in various mucosa and epithelial cells [5,16]. The tri-disulphide motifs in -and -defensins differ [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Defensins have been reported to exhibit powerful antibacterial, antifungal and antiviral activity against a wide variety of microorganisms [17][18][19]. The antibiotic activity of defensins has generally been attributed to their effects on microbial membranes [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…The antibiotic activity of defensins has generally been attributed to their effects on microbial membranes [19,20]. They have been reported to interact with lipopolysaccharides in Gram-negative bacteria, polysaccharides (teichoic acid) in Grampositive bacteria, and phospholipids [17]. The three-dimensional structures of a few defensin peptides have been reported in the crystalline state [21] and in solution [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Large-scale synthesis and functional elements for the antimicrobial activity of defensins

Raj

Antonyraj

Karunakaran

2000

Biochemical Journal

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Human neutrophil defensins, and their analogues incorporating anionic, hydrophobic or cationic residues at the N- and C-termini, were synthesized by solid-phase procedures. The synthetic defensins were examined for their microbicidal activity against Candida albicans, two Gram-negative bacteria (Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis) and two Gram-positive bacteria (Streptococcus gordonii and Streptococcus mutans). The human neutrophil peptide 1 (HNP1) and HNP2 were found to be potent candidacidal agents. HNP3, which differs by one amino acid at the N-terminus of its sequence, was totally inactive. The Gram-negative bacteria A. actinomycetemcomitans and P. gingivalis and the Gram-positive bacteria S. gordonii and S. mutans were insensitive to human defensins. However, the insertion of two basic residues, such as arginine, at both the N-terminus and the C-terminus of HNP2 significantly enhanced antifungal and antibacterial activity. The addition of anionic residues, such as aspartic acid, at the N- and C-termini rendered the molecule totally inactive. The presence of two hydrophobic amino acids, such as valine, at the N-terminus of HNP2 and of two basic arginine residues at its C-terminus resulted in molecules that were optimally active against these oral pathogens. The results suggest that the N- and C-terminal residues in defensin peptides are the crucial functional elements that determine their microbicidal potency. The three-dimensional structure of all defensins constitutes the same amphiphilic β-sheet structure, with the polar face formed by the N- and C-terminal residues playing an important role in defining microbicidal potency and the antimicrobial spectrum. The enhanced microbicidal activity observed for defensin peptides with two basic residues at both the N- and C-termini could be due to optimization of the amphiphilicity of the structure, which could facilitate specific interactions with the microbial membranes.

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“…The role of these natural antibiotics is only just beginning to be appreciated, with potential applications for enhanced natural expression or as new therapeutic agents. Their role may be especially important for the oral cavity in which there is constant exposure to microbial challenges Weinberg et al, 1998). Further, individual variation in expression may contribute to disease susceptibility.…”

Section: Dale and Fredericksmentioning

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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Epithelial Antimicrobial Peptides: Review and Significance for Oral Applications

Cited by 225 publications

References 79 publications

Cloning and Characterization of the Gene for a New Epithelial β-Defensin

Cloning and Characterization of the Gene for a New Epithelial β-Defensin

Large-scale synthesis and functional elements for the antimicrobial activity of defensins

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

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