Current status of defensins and their role in innate and adaptive immunity (original) (raw)
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Defensins: antimicrobial peptides of innate immunity
Nature Reviews Immunology, 2003
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.
Mammalian defensins in the antimicrobial immune response
Nature Immunology, 2005
Defensins are peptidic components of the innate immune system of plants and animals. In mammals, defensins have evolved to have a central function in the host defense properties of granulocytic leukocytes, mucosal surfaces, skin and other epithelia. This review focuses on the biological functions of three structural subgroups of mammalian defensins and the evidence for their involvement as effectors of antimicrobial innate immunity.
Defensins in innate antiviral immunity
2006
The innate immune system provides the first line of defence against a wide range of microorganisms before the development of adaptive immune responses. Toll-like receptors (TLRs) are pattern-recognition receptors that have an important role in the innate immune response. They act as initiators of the innate immune response by providing the host with the ability to recognize pathogenassociated molecular patterns (PAMPs) 1. By contrast, antimicrobial peptides function as important effectors of innate immunity 2. The roles of these two arms of innate immunity in the control of viral infection have recently been recognized 3,4. In this Review, we discuss the antiviral activity of antimicrobial peptides. Antimicrobial peptides, such as defensins and cathelicidins (BOX 1), are small molecules that are mainly produced by leukocytes and epithelial cells. These peptides have a broad range of actions against microorganisms, including Gram-positive and Gram-negative bacteria, fungi and viruses 5-8. Although the antiviral activity of defensins was first reported in 1986 (REF. 9), recent studies have shed light on the multiple and complex mechanisms by which defensins inhibit viral infection. Defensins can block viral infection by directly acting on the virion or by affecting the target cell and thereby indirectly interfering with viral infection. Furthermore, defensin production can be induced by cytokines or TLR activation, and can modulate adaptive immune responses. This Review focuses on the antiviral functions of mammalian defensins, and highlights the recent advances in our understanding of the molecular mechanisms of their antiviral activities and the potential clinical relevance of these functions. An overview of mammalian defensins Classification and structure. Defensins are cysteine-rich, cationic peptides with β-pleated sheet structures that are stabilized by three intramolecular disulphide bonds between the cysteine residues 7,10. Mammalian defensins are classified into three subfamilies, the α-, βand θ-defensins, which differ in their distribution of and disulphide links (bonds) between the six conserved cysteine residues. The disulphide linkages of cysteine residues in α-defensins are between the first and the sixth cysteine residues (Cys 1-Cys 6), Cys 2-Cys 4 and Cys 3-Cys 5 , whereas in β-defensins, the linkages are Cys 1-Cys 5 , Cys 2-Cys 4 and Cys 3-Cys 6. By contrast, θ-defensins have a circular structure with the cysteine residues linked as Cys 1-Cys 6 , Cys 2-Cys 5 and Cys 3-Cys 4 (REF. 11). The α-defensins are synthesized as prepropeptides, which contain an amino-terminal signal sequence, an anionic propiece and a carboxy-terminal mature peptide of approximately 30 amino acids 7. Human α-defensin-1,-2,-3 and-4 are also designated as human neutrophil peptides (HNP1, HNP2, HNP3 and HNP4) because they are mainly expressed by neutrophils 12. HNP1, HNP2 and HNP3 are synthesized by promyelocytes, which are neutrophil precursor cells in the bone marrow, and the mature peptides are stored in primary granules of neutrophils 7. Unlike HNPs, human α-defensin-5 (HD5) is released as a propeptide that is processed extracellularly 13,14. The θ-defensins are composed of two α-defensin-like precursor peptides of nine amino acids that are connected by a post-translational head-to-tail ligation 11,15,16. The contribution of defensin structure to defensin function might vary depending on the function. For example, disulphide bonds are not required for the antibacterial functions of HNP1, human β-defensin-3 (HBD3) and the mouse Paneth-cell-derived α-defensin cryptdin-4 (REFS 17-19). However, having the correct disulphide bonding is important for the chemotactic activity that has been attributed to HBD3 (REF. 18). Similarly, the direct effect of the α-defensin HNP1 or θ-defensins on the virion is abolished when disulphide
Defensins: Transcriptional regulation and function beyond antimicrobial activity
2019
Defensins are one the largest group of antimicrobial peptides and are part of the innate defence. Defensins are produced by animals, plants and fungi. In animals and plants, defensins can be constitutively or differentially expressed both locally or systemically which confer defence before and a stronger response after infection. Immune signalling pathways regulate the gene expression of defensins. These pathways include cellular receptors , which recognise pathogen-associated molecular patterns and are found both in plants and animals. After recognition, signalling pathways and, subsequently, transcriptional factors are activated. There is an increasing number of novel functions in defensins, such as immunomodulators and immune cell attractors. Identification of defensin triggers could help us to elucidate other new functions. The present article reviews the different elicitors of defensins with a main focus on human, fish and marine invertebrate defensins.
Roles of antimicrobial peptides such as defensins in innate and adaptive immunity
Annals of the Rheumatic Diseases, 2003
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Role of defensins in innate immunity
Journal of Shifa Tameer-e-Millat University, 2021
Immune system of living organisms ranging from fungi, plants, vertebrates and invertebrates are all aided by polypeptide chains like defensins and cathelicidins. In humans the defensisns are quite fundamental part of innate immune system in combating with day-to-day exposure to unknown pathogens. The defensins are classified as alpha beta and sigma defensins expressed at chromosome 8 at nearly same positions, the sigma defensin is however synthetically developed as reterocyclin, as it has been stopped producing because of evolutionary development of stop codon 7.5 million years ago. The expression of Defensins can be either constitutive or inducible through epithelial cells, Paneth cells or other respective immune cells to regulate the activation of the innate immune responses. These impart their role either by direct microbicidal action, antiviral activity, inactivation or neutralization of microbial products, mobilization or activation of phagocytes and mast cells. Further to this...
Defensins: antifungal lessons from eukaryotes
Frontiers in Microbiology, 2014
Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed.
Antimicrobial Agents and Chemotherapy, 2007
Beta defensins comprise a family of cationic, cysteine-rich antimicrobial peptides, predominantly expressed at epithelial surfaces. Previously we identified a unique five-cysteine defensin-related peptide (Defr1) that, when synthesized, is a mixture of dimeric isoforms and exhibits potent antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa. Here we report that Defr1 displays antimicrobial activity against an extended panel of multidrug-resistant nosocomial pathogens for which antimicrobial treatment is limited or nonexistent. Defr1 fractions were collected by high-pressure liquid chromatography and analyzed by gel electrophoresis and mass spectrometry. Antimicrobial activity was initially investigated with the type strain Pseudomonas aeruginosa PAO1. All fractions tested displayed equivalent, potent antimicrobial activity levels comparable with that of the unfractionated Defr1. However, use of an oxidized, monomeric six-cysteine analogue (Defr1 Y5C), or of reduced Defr1, gave diminished antimicrobial activity. These results suggest that the covalent dimer structure of Defr1 is crucial to antimicrobial activity; this hypothesis was confirmed by investigation of a synthetic one-cysteine variant (Defr1-1cys). This gave an activity profile similar to that of synthetic Defr1 but only in an oxidized, dimeric form. Thus, we have shown that covalent, dimeric molecules based on the Defr1 -defensin sequence demonstrate antimicrobial activity even in the absence of the canonical cysteine motif.