Role Of Antimicrobial Peptides Research Articles

The Role of Antimicrobial Peptides in Human Skin and in Skin Infectious Diseases

Antimicrobial peptides or proteins (AMPs) represent an ancient and efficient innate defense mechanism which protects interfaces from infection with pathogenic microorganisms. In human skin AMPs are produced mainly by keratinocytes, neutrophils, sebocytes or sweat glands and are either expressed constitutively or after an inflammatory stimulus. In several human skin diseases there is an inverse correlation between severity of the disease and the level of AMP production. Skin lesions of patients with atopic dermatitis show a diminished expression of the beta-defensins and the cathelicidin LL-37. Furthermore, these patients have a reduced amount of the AMP dermcidin in their sweat which correlates with an impaired innate defense of human skin in vivo. In addition, decreased levels of AMPs are associated with burns and chronic wounds. In contrast, overexpression of AMPs can lead to increased protection against skin infections as seen in patients with psoriasis and rosacea, inflammatory skin-diseases which rarely result in superinfection. In other skin diseases, e.g. in patients with acne vulgaris, increased levels of AMPs are often found in inflamed or infected skin areas indicating a role of these peptides in the protection from infection. These data indicate that AMPs have a therapeutical potential as topical anti-infectives in several skin diseases. The broad spectrum of antimicrobial activity, the low incidence of bacterial resistance and their function as immunomodulatory agents are attractive features of AMPs for their clinical use.

137 Expression of Cathelicidin (LL-37) in Thermal Injury

Sepsis remains a common and serious complication of major burn injury and currently accounts for over 54% of deaths in burn patients. Burns have been associated with high levels of circulating proinflammatory cytokines and immunosuppression which promotes systemic inflammatory response syndrome (SIRS) and sepsis, for which no effective treatment is currently available. Defensins and cathelicidins, a family of cationic naturally occurring antimicrobial peptides, are considered important components of the innate immune system as they play a major role in the body’s defense by inhibiting several bacteria, fungi and enveloped viruses. Our prior studies using RT-PCR and fluorescence deconvolution microscopy suggest decreased expression of human β defensin 2 (HBD2) in burn wounds. In this study we have characterized cathelicidin (LL-37) protein levels using in representative skin samples of deep partial and full thickness burns and in unburned skin. Our results show that in unburned skin, the majority of LL-37 was located in the malphigian layer and was concentrated on the stratum corneum as well as colocalized with sweat ducts. In burned skin, in which the epidermis was destroyed, this pattern of LL-37 was absent. The surviving dermal and subcutaneous layers revealed LL-37 presence in very high concentrations colocalized with sweat duct epithelia. The result of these studies will contribute to an understanding of the role of antimicrobial peptides in the pathophysiology of burn injury, associated immunosuppression, and sepsis.

Antimicrobial Peptides in Burns and Wounds

Burn-induced immunosuppression not only increases susceptibility to infection, but also predisposes burn patients to related adverse sequelae, including systemic inflammatory response syndrome and sepsis. Although burn-related immunosuppression is not fully understood, it is characterized by decreased T- and B-lymphocyte function and by impaired functions of circulating leukocytes and complement. Alterations in defensins, a family of cationic, naturally occurring antimicrobial peptides, may underlie these immune deficiency patterns. Defensins are considered important components of the innate immune system, as they inhibit bacterial, fungal, and viral colonization. They also chemoattract immature dendritic cells and T lymphocytes, recruit neutrophils, macrophages, and monocytes, modulate complement and adjuvant activity, and promote inflammation and wound healing. Infectious states are associated with upregulation of circulating defensins, which suggests an underlying antimicrobial role. In addition, data from our laboratory demonstrated diminished levels of certain defensins in burned tissue. The inference is that decreased defensin levels in burn injury may facilitate infection and subsequent sepsis. It may also alter functions of T- and B-lymphocytes, neutrophils, macrophages, and complement, thereby contributing to the pathophysiology of burn-related systemic inflammatory responses. This article is a comprehensive review on the role of antimicrobial peptides in burns and wounds.

The role of human beta defensins and cathelicidins in atopic dermatitis

Atopic dermatitis is a chronic inflammatory skin disease associated with significant barrier disruption, T-helper type 2 mediated skin inflammation, and an impaired innate immune response. These characteristics increase the susceptibility of atopic dermatitis patients to recurrent skin infections, some of which may have potentially fatal implications. The mechanisms resulting in this increased propensity for skin infections have been an area of active investigation. Antimicrobial peptides are an integral component of the innate immune response due to their broad spectrum activity against invading pathogens. Recent studies have shown that these peptides are effective at killing Staphylococcus aureus, herpes simplex virus, vaccinia virus, and the Malassezia species, pathogens associated with significant morbidity in patients with atopic dermatitis. Additionally, these peptides are deficient in the skin of atopic dermatitis patients, suggesting that the increased propensity of patients towards skin infection is due to the lack of antimicrobial peptide expression. The current review will examine recent literature on the role of antimicrobial peptides in atopic dermatitis in an effort to improve our understanding of why patients with the condition suffer from recurrent infections.

Biological characterization and modes of action of temporins and bombinins H, multiple forms of short and mildly cationic anti‐microbial peptides from amphibian skin

Genetically encoded cationic anti-microbial peptides (AMPs) are essential components of the ancient and non-specific innate immune system, which is the principal defence mechanism of all species of life, with the primary role to kill infectious microorganisms. Amphibian skin is one of the richest natural sources of such molecules, which are produced by holocrine-type dermal glands and released upon stimulation. This review highlights the attractive and unique structural/functional properties of temporins and bombinins H, two families of short and mildly cationic peptides, isolated from the skin of frogs belonging to Rana and Bombina genera, respectively. Beside improving our knowledge on the role of AMPs in the regulation of the innate immunity, the biological significance of the existence of multiple forms of a prototypic peptide sequence within the same organism and the implication of short peptides in the endotoxin neutralization, these two classes of AMPs can be also considered as valid candidates for the design of novel anti-infective and anti-sepsis drugs.

The role of antimicrobial peptides and proteins in keratinocyte defense

The role of antimicrobial peptides and proteins in keratinocyte defense

Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages

Antimicrobial peptides (AMPs), in addition to their antibacterial properties, are also chemotactic and signalling molecules that connect the innate and adaptive immune responses. The role of AMP [alpha defensins, LL-37, a cathepsin G-derived peptide (CG117-136), protegrins (PG-1), polymyxin B (PMX) and LLP1] in modulating the respiratory burst response in human and murine macrophages in the presence of bacterial endotoxin [lipopolysaccharide (LPS) or lipooligosaccharide (LOS)] was investigated. AMP were found to neutralize endotoxin induction of nitric oxide and TNFalpha release in macrophages in a dose-dependent manner. In contrast, macrophages primed overnight with AMP and LOS or LPS significantly enhanced reactive oxygen species (ROS) release compared with cells primed with endotoxin or AMP alone, while no responses were seen in unprimed cells. This enhanced ROS release by macrophages was seen in all cell lines including those obtained from C3H/HeJ (TLR4-/-) mice. Similar effects were also seen when AMP and endotoxin were added directly with zymosan to trigger phagocytosis and the respiratory burst in unprimed RAW 264.7 and C3H/HeJ macrophages. Amplification of ROS release was also demonstrated in a cell-free system of xanthine and xanthine oxidase. Although AMP inhibited cytokine and nitric oxide induction by endotoxin in a TLR4-dependent manner, AMP and endotoxin amplified ROS release in a TLR4-independent manner possibly by exerting a prolonged catalytic effect on the ROS generating enzymes such as the NADPH-oxidase complex.

Detection of individual human neutrophil α-defensins (human neutrophil peptides 1, 2 and 3) in unfractionated gingival crevicular fluid—A MALDI-MS approach

The role of antimicrobial peptides is particularly important in the oral cavity where there is constant challenge by microorganisms. The α-defensins are a group of cationic peptides that comprise 30–50% of the total protein in azurophilic granules of human neutrophils. They include the human neutrophil peptides (HNP) 1, 2 and 3 which have almost identical amino acid sequences but differ in their biological activities. The amino acid sequence similarities of the defensins have made it difficult to unequivocally determine the presence of individual defensins using antibody-based techniques. However, by virtue of their cationic nature we postulated that the defensins would fly particularly well in mass spectrometry and that this characteristic would allow facile identification of individual HNPs in unfractionated gingival crevicular fluid (GCF) from periodontitis patients and healthy controls. Although there was variability in levels of defensins detected in periodontal health and disease, HNP-1 was always identified as the major peak in the triad and HNP-3 as the minor peak, lending support to the hypothesis that HNP-2 may arise by post-translational proteoyltic cleavage of HNP-3 rather than HNP-1. The finding that the defensins were more abundant in a higher proportion of the healthy sites studied could be linked to a more intact defensin barrier in periodontal health.

The dual role of antimicrobial peptides - antibiotic activity and endotoxin neutralization

The dual role of antimicrobial peptides - antibiotic activity and endotoxin neutralization

The Role of Antimicrobial Peptides in Innate Immunity

Production of antimicrobial peptides and proteins is an important means of host defense in eukaryotes. The larger antimicrobial proteins, containing more than 100 amino acids, are often lytic enzymes, nutrient-binding proteins or contain sites that target specific microbial macromolecules. The smaller antimicrobial peptides act largely by disrupting the structure or function of microbial cell membranes. Hundreds of antimicrobial peptides have been found in the epithelial layers, phagocytic cells and body fluids of multicellular animals, from mollusks to humans. Some antimicrobial peptides are produced constitutively, others are induced in response to infection or inflammation. Studies of the regulation of antimicrobial peptide synthesis in Drosophila have been particularly fruitful, and have provided a new paradigm for the analysis of mammalian host defense responses. It now appears that the general patterns of antimicrobial responses of invertebrates have been preserved in vertebrates ("innate immunity") where they contribute to host defense both independently and in complex interplay with adaptive immunity.

The role of antimicrobial peptides in animal defenses.

It is becoming clear that the cationic antimicrobial peptides are an important component of the innate defenses of all species of life. Such peptides can be constitutively expressed or induced by bacteria or their products. The best peptides have good activities vs. a broad range of bacterial strains, including antibiotic-resistant isolates. They kill very rapidly, do not easily select resistant mutants, are synergistic with conventional antibiotics, other peptides, and lysozyme, and are able to kill bacteria in animal models. It is known that bacterial infections, especially when treated with antibiotics, can lead to the release of bacterial products such as lipopolysaccharide (LPS) and lipoteichoic acid, resulting in potentially lethal sepsis. In contrast to antibiotics, the peptides actually prevent cytokine induction by bacterial products in tissue culture and human blood, and they block the onset of sepsis in mouse models of endotoxemia. Consistent with this, transcriptional gene array experiments using a macrophage cell line demonstrated that a model peptide, CEMA, blocks the expression of many genes whose transcription was induced by LPS. The peptides do this in part by blocking LPS interaction with the serum protein LBP. In addition, CEMA itself has a direct effect on macrophage gene expression. Because cationic antimicrobial peptides are induced by LPS and are able to dampen the septic response of animal cells to LPS, we propose that, in addition to their role in direct and lysozyme-assisted killing of microbes, they have a role in feedback regulation of cytokine responses. We are currently developing variant peptides as therapeutics against antibiotic-resistant infections.

Flora: Role in Colonisation Resistance and Other Effects; Production of Antimicrobial Peptides

This communication describes the innate immunity, activated upon exposure to foreign antigens without prior priming, and the role of antimicrobial peptides in this system. The focus will be on peptides produced by gastrointestinal cells (Paneth cells). Possible applications for the pharmaceutical industry of these alternatives to antibiotics are discussed.

Flora: Role in Colonisation Resistance and Other Effects; Production of Antimicrobial Peptides

This communication describes the innate immunity, activated upon exposure to foreign antigens without prior priming, and the role of antimicrobial peptides in this system. The focus will be on peptides produced by gastrointestinal cells (Paneth cells). Possible applications for the pharmaceutical industry of these alternatives to antibiotics are discussed.

Epithelial Antibiotics Induced at Sites of Inflammation

The role of antimicrobial peptides in epithelial defense is not fully understood. An epithelial beta-defensin, lingual antimicrobial peptide (LAP), was isolated from bovine tongue and the corresponding complementary DNA cloned. LAP showed a broad spectrum of antibacterial and antifungal activities. LAP messenger RNA abundance was markedly increased in the epithelium surrounding naturally occurring tongue lesions. This increase coincided with the cellular hallmarks of acute and chronic inflammation in the underlying lamina propria, supporting a role for epithelial antimicrobial peptides as integral components of the inflammatory response.