Defensins: antimicrobial peptides of innate immunity.
TL;DR: This review, inspired by a spate of recent studies ofdefensins in human diseases and animal models, focuses on the biological function of defensins.
Abstract: The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.
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TL;DR: In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented and several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibits protein synthesis or inhibit enzymatic activity.
Abstract: Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by 'barrel-stave', 'carpet' or 'toroidal-pore' mechanisms. Although these models are helpful for defining mechanisms of antimicrobial peptide activity, their relevance to how peptides damage and kill microorganisms still need to be clarified. Recently, there has been speculation that transmembrane pore formation is not the only mechanism of microbial killing. In fact several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity. In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented.
5,102 citations
TL;DR: Known discrepancies in both innate and adaptive immunity are outlined, including balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets andChemokine and chemokine receptor expression.
Abstract: Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
3,098 citations
Cites background from "Defensins: antimicrobial peptides o..."
...These are important in mucosal defense in the gut and in epithelial defense in skin and elsewhere (12, 13)....
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TL;DR: The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides.
Abstract: Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents.
2,231 citations
Cites background from "Defensins: antimicrobial peptides o..."
...A second prominent group of mammalian antimicrobial peptides is the defensins (70, 221), cyclic peptides which are categorized into three subfamilies on the basis of the disulfide pairings between their six conserved cysteine residues ( - and -defensins) or their macrocyclic nature ( -defensins)....
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TL;DR: It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes and the role of theMPO system in tissue injury.
Abstract: Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes.
2,070 citations
Additional excerpts
...These include defensins, seprocidins, bactericidal/permeability-increasing protein, lysozyme, cathelicidins, phospholipase A2, and lactoferrin [339–342]....
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TL;DR: Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase, but this is incorrect.
Abstract: Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.
1,672 citations
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TL;DR: This review, which is focused on the different stages of membrane permeation induced by representatives of amphipathic alpha-helical antimicrobial and cell non-selective lytic peptides distinguishes between the 'carpet' mechanism, which holds for antimicrobial peptides versus the 'barrel-stave' mechanisms, which hold for cellnon- selective lytics peptides.
1,790 citations
"Defensins: antimicrobial peptides o..." refers background in this paper
...Most biophysical studies on the mode of action of antimicrobial peptides have used simple α-helical (for example, magainin and cecropin) or β-loop (for example, protegrin) peptide...
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TL;DR: In this paper, human β-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells.
Abstract: Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human β-defensins are also chemotactic for immature dendritic cells and memory T cells. Human β-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The β-defensin–induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by β-defensin. Thus, β-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.
1,766 citations
"Defensins: antimicrobial peptides o..." refers background in this paper
...Other activities of defensins Various defensins have been reported to have chemotactic activity for monocytes, T cells and dendritic cell...
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TL;DR: The defensin system may operate in conjunction with or independently from oxygen-dependent microbicidal processes to enable human neutrophils to inactivate and destroy potential pathogens.
Abstract: We extracted a granule-rich sediment from normal human neutrophils and subjected it to chromatographic, electrophoretic, and functional analysis. The extract contained three small (molecular weight less than 3,500) antibiotic peptides that were named human neutrophil peptide (HNP)-1, HNP-2, and HNP-3, and which will be referred to as "defensins." HNP 1-3, a mixture of the three defensins, killed Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli effectively in vitro when tested in 10 mM phosphate buffer containing certain nutrients, but it had little or no bactericidal activity in nutrient-free buffer. In contrast, the nutrient-free buffer supported a high degree of activity by HNP 1-3 against Cryptococcus neoformans. In addition to its antibacterial and antifungal properties, HNP 1-3 directly inactivated herpes simplex virus, Type 1. Two of the individual purified defensins, HNP-1 and HNP-2, were as microbicidal as the mixture HNP 1-3. HNP-3 was less active than the other defensins against most but not all of the microbes tested. Immunoperoxidase stains revealed HNP 1-3 to have a granular localization in the neutrophil's cytoplasm by light microscopy. Frozen thin section immunogold transmission electron microscopy showed HNP 1-3 to be localized in azurophil granules. These studies define a broad-spectrum antimicrobial system in human neutrophils. The defensin system may operate in conjunction with or independently from oxygen-dependent microbicidal processes to enable human neutrophils to inactivate and destroy potential pathogens.
1,372 citations
TL;DR: It is reported that human skin is protected in a similar way by an inducible, transcriptionally regulated, antibiotic peptide, which resembles those in other mammals.
Abstract: To avoid opportunistic infections, plants and animals have developed antimicrobial peptides in their epithelia that can form pores in the cytoplasmic membrane of microorganisms1. After contact with microorganisms, vertebrate skin2, trachea and tongue epithelia3 are rich sources of peptide antibiotics1, which may explain the unexpected resistance of these tissues to infection. Here we report that human skin is protected in a similar way by an inducible, transcriptionally regulated, antibiotic peptide, which resembles those in other mammals.
1,336 citations
TL;DR: Human β-defensin-3, hBD-3 demonstrated a salt-insensitive broad spectrum of potent antimicrobial activity against many potentially pathogenic microbes including multiresistant S. aureus and vancomycin-resistant Enterococcus faecium.
1,318 citations