Lipid-Specific Membrane Activity of Human β-Defensin-3

Abstract

Defensins represent a major component of innate host defense against bacteria, fungi, and enveloped viruses. One potent defensin found, e.g., in epithelia, is the polycationic human beta-defensin-3 (hBD3). We investigated the role of the lipid matrix composition, and in particular the presence of negatively charged lipopolysaccharides (LPS) from sensitive (Escherichia coli, Salmonella enterica serovar Minnesota) or resistant (Proteus mirabilis) Gram-negative bacteria or of the zwitterionic phospholipids of human cells, in determining the action of polycationic hBD3 on the different membranes, and related to their biological activity. The main focus was directed on data derived from electrical measurements on a reconstitution system of the OM as a planar asymmetric bilayer composed on one side of LPS and on the other of a phospholipid mixture. Our results demonstrate that the antimicrobial activity and the absence of cytotoxicity can be explained by the lipid-specificity of the peptide. A clear correlation between these aspects of the biological activity of hBD3 and its interaction with lipid matrices could be found. In particular, hBD3 could only induce lesions in those membranes resembling the lipid composition of the OM of sensitive bacterial strains. The permeation through the membrane is a decisive first step for the biological activity of many antimicrobial peptides. Therefore, we propose that the lipid-specificity of hBD3 as well as some other membrane-active antimicrobial peptides is important for their activity against bacteria or mammalian cells.

Role of Human β-Defensin-2 during Tumor Necrosis Factor-α/NF-κB-mediated Innate Antiviral Response against Human Respiratory Syncytial Virus

“…6). Similar properties of HBD2 and HBD3 were previously reported because they disrupted bacterial cell wall and lipid bilayers (41)(42)(43)(44). In case of HIV-1, HBD3 also conferred its antiviral activity by down-regulating cell surface expression of HIV-1 receptor CXCR4 (81).…”

“…HBDs are known to play an important role in innate immune response by virtue of their potent antimicrobial activity against Gram-negative and Gram-positive bacteria. HBDs are highly cationic, and it is suggested that the amphipathic character of HBDs is responsible for their antimicrobial activity, because they can interact with the bacterial membrane (by interacting with the negatively charged phospholipids of the bacterial membrane) leading to permeabilization (disruption of cell wall) and release of cellular contents (11)(12)(13)(41)(42)(43)(44). The three well established HBDs belonging to the ␤-defensin family of polypeptides are HBD1, HBD2, and HBD3.…”

“…2), it was also shown that incubation of HIV-1 virion particles with HBD2 and HBD3 renders less infectious virus presumably because of permeabilization of the viral envelope lipid bilayer by the cationic ␤-defensin proteins (22,34). Indeed, HBD2 and HBD3 are capable of disrupting both artificial lipid bilayers and bacterial cell wall (41)(42)(43)(44). To examine the effect of HBDs on viral envelope integrity, purified RSV virions (0.2 m.o.i.)…”

Analysis and Separation of Residues Important for the Chemoattractant and Antimicrobial Activities of β-Defensin 3

“…HBD1 to -3). N-terminal regions of defensins are often more aliphatic, and since helices are a frequent structural motif in antimicrobial peptides, it is likely that this is the region of the peptide that directs membrane insertion and disruption (37). It is also interesting to note that D14ip1 contains within it a stretch of eight amino acids (GGRAAVLN), which are identical to the XT4 peptide fragment of an antimicrobial peptide isolated from the skin secretions of the diploid frog (38).…”

Human α- and β-Defensins Bind to Immobilized Adhesins fromPorphyromonas gingivalis

“…They kill gram-negative bacteria, gram-positive bacteria, and fungi and inhibit some viral infections (18,21,25,28,48); chemoattract monocytes, macrophages, CD45 RA ϩ /CD4 ϩ T lymphocytes, mast cells, and immature dendritic cells (10,21,62); enhance antigen-specific immune responses (9,38); and even possibly regulate pigmentation and body weight via modulation of Mc1r and Mc4r (1). Defensins also bind to bacterial membranes (7,17) and lipopolysaccharides (17,39) and neutralize select bacterial toxins (23,31,32). Binding of human neutrophil peptide ␣-defensins (HNPs) and human ␤-defensins (HBDs) to these materials may facilitate receptor-mediated internalization of microbial antigens to immature dendritic cells (61) or attenuate antigen-induced proinflammatory cytokine responses (44).…”