Functions of Antimicrobial Peptides in Host Defense and Immunity

Beißwenger, Christoph; Bals, Robert

doi:10.2174/1389203054065428

Cited by 102 publications

(68 citation statements)

References 136 publications

(159 reference statements)

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“…Overall, the data on snap-frozen patient tissue biopsy specimens revealed a significant correlation between neutrophil infiltration and severely involved tissue characterized by high inflammation. It is becoming increasingly evident that many of the antimicrobial peptides act not only as antimicrobial agents but also as significant mediators of other biological effects, including immunomodulatory and chemotactic activities (3,12). Mature LL-37 has been shown to have chemotactic activity for neutrophils and CD4 T cells (1,22).…”

Section: Resultsmentioning

confidence: 99%

“…The immunomodulatory properties of the bacteria include, among others, avoidance and modulation of host innate defense mechanisms. A central component of the first line of defense is the antimicrobial peptides expressed in epithelia and several of the innate immune cells (3). Cathelicidins are cationic antimicrobial peptides, referred to as LL-37 and CRAMP in humans and mice, respectively, that exert their antimicrobial activity through disruption of bacterial membranes, resulting in cell lysis (8,16).…”

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confidence: 99%

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Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans

et al. 2008

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Severe soft tissue infections, such as necrotizing fasciitis and severe cellulitis, caused by group A streptococci (GAS) are rapidly progressing life-threatening infections characterized by massive bacterial loads in the tissue even late after the onset of infection. Antimicrobial peptides are important components of the innate host defense, and cathelicidins have been shown to protect against murine necrotic skin infections caused by GAS. However, it has been demonstrated that the streptococcal cysteine protease SpeB proteolytically inactivates the human cathelicidin LL-37 in vitro. Here we have investigated the expression of LL-37 and its interaction with GAS and SpeB during acute severe soft tissue infections by analyses of patient tissue biopsy specimens. The results showed large amounts of LL-37, both the proform (hCAP18) and the mature peptide, in the tissue. Confocal microscopy identified neutrophils as the main source of the peptide. A distinct colocalization between the bacteria and LL-37 could be noted, and bacterial loads showed positive correlation to the LL-37 levels. Areas with high LL-37 levels coincided with areas with large amounts of SpeB. Confocal microscopy confirmed strong colocalization of GAS, SpeB, and LL-37 at the bacterial surface. Taken together, the findings of this study provide in vivo support of the hypothesis that SpeB-mediated inactivation of LL-37 at the streptococcal surface represents a bacterial resistance mechanism at the infected tissue site in patients with severe GAS tissue infections.

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Section: Resultsmentioning

confidence: 99%

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Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans

et al. 2008

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“…The soluble factors expressed by most organisms to kill bacteria are sufficiently general to prevent not only bacterial growth but also bacterial resistance. These factors, known in mammals as cationic antimicrobial peptides (CAPs), are small peptides derived by posttranslational and often extracellular cleavage of precursor proteins that can have functions independent of the antibacterial activity of their cleavage products (3,7,28). The relative lack of specificity of CAPs is essential to their general effectiveness and possible lack of bacterial resistance (24).…”

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confidence: 99%

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Bucki

Leszczyńska²,

Byfield

et al. 2010

Antimicrob Agents Chemother

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The rising number of antibiotic-resistant bacterial strains represents an emerging health problem that has motivated efforts to develop new antibacterial agents. Endogenous cationic antibacterial peptides (CAPs) that are produced in tissues exposed to the external environment are one model for the design of novel antibacterial compounds. Here, we report evidence that disubstituted dexamethasone-spermine (D2S), a cationic corticosteroid derivative initially identified as a by-product of synthesis of dexamethasone-spermine (

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“…Defensins are recognized as an important element of the human innate immune system (1)(2)(3)(4). The defensin family is composed of small (3-5 kDa), cationic, and cysteine-rich proteins.…”

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Studies of the Biological Properties of Human β-Defensin 1

Pazgier

Prahl²,

Hoover³

et al. 2007

Journal of Biological Chemistry

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Defensins are small (30 -45 amino acid residues) cationic proteins with broad antimicrobial activity against many bacteria and fungi, some enveloped viruses, and other activities such as chemoattraction of a range of different cell types to the sites of inflammation. These proteins represent attractive targets for developing novel antimicrobial agents and modulators of immune responses with therapeutic applicability. In this report, we present the results of functional and structural studies of 26 single-site mutants of human ␤-defensin 1 (hBD1). All mutants were assayed for antimicrobial activity against Escherichia coli (ATCC strain 25922) and for chemotactic activity with CCR6-transfected HEK293 cells. To analyze the structural implications of mutagenesis and to verify the correctness of the disulfide connectivity, we used x-ray crystallography to conduct complete structural studies for 10 mutants in which the topology of disulfides was the same as in the native hBD1. Mutations did not induce significant changes of the tertiary structure, suggesting that the observed alterations of biological properties of the mutants were solely associated with changes in the respective side chains. We found that cationic residues located near the C terminus (Arg Defensins are recognized as an important element of the human innate immune system (1-4). The defensin family is composed of small (3-5 kDa), cationic, and cysteine-rich proteins. In human defensins, the connectivity of three disulfide bridges forms the basis for assigning them into one of two classes, the ␣-and ␤-defensins (5-7). In ␤-defensins, the topology of the three disulfide bridges is 1-5, 2-4, and 3-6, meaning that the first cysteine in the sequence is covalently linked to the fifth, and so on. Three human ␤-defensins, hBD1-3, 4 have been isolated from natural sources and characterized in detail (8 -11). Additionally, the recombinant or synthetic preparations of hBD4, hBD27, and hBD28 have also been described and characterized functionally (12, 13). Analysis of the human genome indicates the existence of over 40 potential coding regions for these peptides (14,15).In addition to broad antimicrobial activity, hBDs have also been recognized as modulators of cell-mediated adaptive immunity, due to their chemotactic and immunoenhancing activity (16 -19). Recent studies revealed that ␤-defensins also play a role in cell differentiation, tissue remodeling, and sperm maturation (20 -22).The first human ␤-defensin to be discovered, hBD1, is constitutively expressed in the epithelial cells of the urinary and respiratory tracts and in keratinocytes of skin (9,23,24). A naturally occurring 36-amino acid hBD1 peptide shows anti-bacterial activity at micromolar concentrations against some Gramnegative bacteria (i.e. Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae), as well as yeast Candida albicans. When tested in vitro, hBD1 is relatively less potent against the Gram-positive Streptococcus aureus (9, 10, 23).HBD1 and hBD2 selectively chemoattract hum...

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Functions of Antimicrobial Peptides in Host Defense and Immunity

Cited by 102 publications

References 136 publications

Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans

Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Studies of the Biological Properties of Human β-Defensin 1

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