Role of defensins in innate immunity (original) (raw)
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Current status of defensins and their role in innate and adaptive immunity
FEMS Microbiology Letters, 2002
Naturally occurring antimicrobial cationic polypeptides play a major role in innate and adaptive immunity. These polypeptides are found to be either linear and unstructured or structured through disulfide bonds. Among the structured antimicrobial polypeptides, defensins comprise a family of cysteine-rich cationic polypeptides that contribute significantly to host defense against the invasion of microorganisms in animals, humans, insects and plants. Their wide-spread occurrence in various tissues of these diverse organisms, and their importance in innate and adaptive immunity have led to their identification, isolation and characterization. A large volume of literature is available on defensins' occurrence, structural characterization, gene expression and regulation under normal and pathological conditions. Much has also been published regarding their antimicrobial, antiviral and chemoattractive properties, and their molecular and cellular interactions. In this review, we describe the current status of our knowledge of defensins with respect to their molecular, cellular and structural biology, their role in host defense, future research paradigms and the possibility of their utilization as a new class of non-toxic antimicrobial agents and immuno-modulators. ß
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.
Frontiers in Immunology, 2015
Defensins represent an evolutionary ancient family of antimicrobial peptides that play diverse roles in human health and disease. Defensins are cationic cysteine-containing multifunctional peptides predominantly expressed by epithelial cells or neutrophils. Defensins play a key role in host innate immune responses to infection and, in addition to their classically described role as antimicrobial peptides, have also been implicated in immune modulation, fertility, development, and wound healing. Aberrant expression of defensins is important in a number of inflammatory diseases as well as modulating host immune responses to bacteria, unicellular pathogens, and viruses. In parallel with their role in immunity, in other species, defensins have evolved alternative functions, including the control of coat color in dogs. Defensin genes reside in complex genomic regions that are prone to structural variations and some defensin family members exhibit copy number variation (CNV). Structural variations have mediated, and continue to influence, the diversification and expression of defensin family members.This review highlights the work currently being done to better understand the genomic architecture of the β-defensin locus. It evaluates current evidence linking defensin CNV to autoimmune disease (i.e., Crohn's disease and psoriasis) as well as the contribution CNV has in influencing immune responses to HIV infection.
Multifaceted immune functions of human defensins and underlying mechanisms
Seminars in cell & developmental biology, 2018
Defensins have been long recognized as natural antimicrobial peptides, but they also possess diverse and versatile immune functions. Defensins can both induce inflammation and suppress inflammatory responses by acting on specific cells through distinct mechanisms. Defensins can also modulate the immune response by forming a complex with cellular molecules including proteins, nucleic acids, and carbohydrates. The mechanisms of defensin-mediated immune modulation appear to be cell-type and context specific. Because the levels of human defensins are often altered in response to infection or disease states, suggesting their clinical relevance, this review summarizes the complex immune functions of human defensins and their underlying mechanisms of action, which have implications for the development of new therapeutics.
Mammalian defensins in immunity: more than just microbicidal
Trends in Immunology, 2002
Mammalian defensins are small, cationic, antimicrobial peptides encoded by the host that are considered to be important antibiotic-like effectors of innate immunity. By using chemokine receptors on dendritic cells and T cells, defensins might also contribute to the regulation of host adaptive immunity against microbial invasion. Defensins have considerable immunological adjuvant activity and linkage of β β-defensins or selected chemokines to an idiotypic lymphoma antigen has yielded potent antitumor vaccines. The functional overlap between defensins and chemokines is reinforced by reports that some chemokines have antimicrobial activities. Although showing similarity in activity and overall tertiary structure, the evolutionary relationship between defensins and chemokines remains to be determined.
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.
Infection and Immunity
beta-Defensins are cationic peptides with broad-spectrum antimicrobial activity that may play a role in mucosal defenses of several organs. They have been isolated in several species, and in humans, two beta-defensins have been identified. Here, we report the identification of two genes encoding beta-defensin homologues in the rat. Partial cDNAs were found by searching the expressed-sequence-tag database, and primers were designed to generate full-length mRNA coding sequences. One gene was highly similar to the human beta-defensin-1 (HBD-1) gene and mouse beta-defensin-1 gene at both the nucleic acid and amino acid levels and was termed rat beta-defensin-1 (RBD-1). The other gene, named RBD-2, was homologous to the HBD-2 and bovine tracheal antimicrobial peptide (TAP) genes. The predicted prepropeptides were strongly cationic, were 69 and 63 residues in length for RBD-1 and RBD-2, respectively, and contained the six-cysteine motif characteristic of beta-defensins. The beta-defensin ...
Roles of antimicrobial peptides such as defensins in innate and adaptive immunity
Annals of the Rheumatic Diseases, 2003
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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