Current status of defensins and their role in innate and adaptive immunity

Abstract

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

Amphiphilic α-Helical Antimicrobial Peptides and Their Structure / Function Relationships

“…These linear relationships imply that a characteristic balance between amphiphilicity and hydrophobicity may be required by each of these groups of α-AMPs to invade the membranes of their respective target organisms. Biophysical studies on the membrane interactions of both novel peptides and modified α-AMPs generally support these latter observations [62] and similar studies involving defensins have suggested that appropriate balances between amphiphilicity and hydrophobicity may be important to the ability of these peptides to invade the membranes of differing target organisms [14]. Further examination of figure 6 shows that the sensitivity of < µH > to changes in < H > decreases significantly in the order {G+, G-}→ {G+, G-F, P} → {G+, G-, F}.…”

“…In contrast to the above, cysteine rich β-sheet AMPs, such as defensins [14], and other conformationally restrained AMPs [23], form a major group of peptides that invade microbial membranes though the use of tertiary amphiphilicity. In this case residues that are distal in the primary structure of a molecule are brought together in its tertiary structure to form polar and apolar surfaces [18], as shown for the human defensin, neutrophil-3, in figure 1.…”

“…It can be seen that the N-terminal and C-terminal residues of this molecule are brought together to form its polar face whilst the folding pattern of its middle region generates the apolar face. Defensins may be taken as representative of tertiary amphiphiles and the sequences and folding patterns of these AMPs varies widely across mammals, insects and plants [14,24], generating a rich spectrum of amphiphilic structures. In this manner, tertiary amphiphilicity has been tailored by AMPs to facilitate microbial membrane invasion and the antimicrobial actions of a structurally diverse range of peptides that are appropriate to the defence needs of an equally diverse range of host organisms [2,14,23,24].…”

“…The "Toroidal pore model (TPM)" assumes that α-AMPs utilise a mode of initial membrane binding and orientation that is similar to that proposed by the BSPM. However, according to the TPM, the aggregation of α-AMPs on the membrane surface imposes a positive curvature strain by Figure 1A was adapted from Raj and Dentino, [14] and illustrates the tertiary amphiphilicity possessed by the β-sheet defensin, human neutrophil-3. The side-chains of residues are not shown for clarity and it can be seen that proximity of N-terminal and C-terminal residues generate the polar face whilst the folding pattern of the molecule's middle region generates the apolar face.…”

“…All AMPs are membrane interactive and whilst the antimicrobial action of some AMPs appears to involve attack on intracellular targets, in most cases, direct attack on the microbial membrane itself is the primary killing mechanism used by these peptides [12,13]. Numerous studies have shown that the invasion of microbial membranes by AMPs leads to a variety of lethal effects, including: membrane depolarisation, permeabilisation and lysis, with these effects generally mediated by the non-specific interaction of AMPs with the membrane lipid matrix rather than membrane proteins [14,15]. To accommodate the inherently amphiphilic nature of the membrane lipid matrix, AMPs themselves have developed a variety of amphiphilic structures.…”