The complement system represents an evolutionary old and significant part of the innate immune system involved in protection against invading microorganisms. Here, we show that the anaphylatoxin C3a and its inactivated derivative C3a-desArg are antibacterial, demonstrating a previously unknown direct antimicrobial effect of complement activation. The C3a peptide, as well as functional epitopes in the sequence, efficiently killed the Gramnegative bacteria Escherichia coli, Pseudomonas aeruginosa, and the Gram-positive Enterococcus faecalis. In mice, a C3a-derived peptide suppressed infection by Gram-positive Streptococcus pyogenes bacteria. Fluorescence and electron microscopy demonstrated that C3a binds to and induces breaks in bacterial membranes. C3a was also found to induce membrane leakage of liposomes. These findings provide an interesting link between the complement system and antimicrobial peptides, which are two important branches of innate immunity.bacteria ͉ inflammation ͉ innate immunity
IdeS is a streptococcal protease that cleaves IgG antibodies into F(ab’)2 and Fc fragments with a unique degree of specificity, thereby providing a novel treatment opportunity of IgG-driven autoimmune conditions and antibody mediated transplant rejection. Here we report the results from a first in man, double blinded and randomized study with single ascending doses of IdeS in healthy, male subjects. Twenty healthy subjects were given intravenous single ascending doses of IdeS. With impressive efficacy IdeS cleaved the entire plasma IgG-pool only minutes after dosing. IgG reached nadir 6-24 hours after dosing and then slowly recovered. The half-life of IdeS was 4.9 (±2.8) hours at 0.24 mg/kg with the main fraction eliminated during 24 hours. Already two hours after IdeS-dosing, the phagocytic capacity of IgG/IgG-fragments was reduced to background levels. Importantly, IdeS has the capacity to inactivate Fc-mediated effector function in vivo, was considered safe with no serious adverse events, and without dose limiting toxicity in this study. The complete, rapid, but temporary removal of IgG provides a new potent therapeutic opportunity in IgG-mediated pathogenic conditions.Trial RegistrationClinicalTrials.gov NCT01802697
Antimicrobial peptides are important effectors of the innate immune system. These peptides belong to a multifunctional group of molecules that apart from their antibacterial activities also interact with mammalian cells and glycosaminoglycans and control chemotaxis, apoptosis, and angiogenesis. Here we demonstrate a novel antimicrobial activity of the heparin-binding and cell-binding domain 5 of high molecular weight kininogen. Antimicrobial epitopes of domain 5 were characterized by analysis of overlapping peptides. A peptide, HKH20 (His 479 -His 498 ), efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and the Gram-positive Enterococcus faecalis. Fluorescence microscopy and electron microscopy demonstrated that HKH20 binds to and induces breaks in bacterial membranes. Furthermore, no discernible hemolysis or membrane-permeabilizing effects on eukaryotic cells were noted. Proteolytic degradation of high molecular weight kininogen by neutrophil-derived proteases as well as the metalloproteinase elastase from P. aeruginosa yielded fragments comprising HKH20 epitopes, indicating that kininogen-derived antibacterial peptides are released during proteolysis.The innate immune system, based on antimicrobial peptides (AMP), 2 provides a rapid and nonspecific response against potentially invasive pathogenic microorganisms. AMPs, first isolated from human leukocyte extracts by Zeya and Spitznagel in 1963 (1), were subsequently discovered in invertebrates (2) and cold-blooded vertebrates (3). At present, over 880 different AMPs have been identified in eukaryotes. During recent years it has become increasingly evident that many antimicrobial peptides are multifunctional (4, 5). They are found to mediate chemotaxis (defensins, LL-37) (6 -8), apoptosis (lactoferricin, LL-37) (9 -11), and angiogenesis (PR-39, LL-37) (12, 13). Conversely, molecules previously not considered as AMPs, including proinflammatory and chemotactic chemokines (14), neuropeptides (15-19), and peptide hormones (16,20), have recently been found to exert antibacterial activities. The proinflammatory, chemotactic, and anaphylatoxic peptide C3a, generated during activation of the complement system, displays potent antibacterial effects (21). Many AMPs, by virtue of their cationicity and amphipathicity, also interact with heparin (22, 23).High molecular weight kininogen (HMWK) is a multifunctional 120-kDa glycoprotein found in plasma (ϳ80 g/ml) (24) and in ␣-granules of platelets (25). The protein is composed of six domains, each having different properties and specific ligands (24). Domains D1-D3 have a cystatin-like structure, and the two latter domains serve as specific inhibitors of cysteine proteinases such as cathepsins and calpains. The D4 domain contains the bradykinin sequence, which is released by plasma kallikreins during contact activation (24, 26). Biologically active kinins can also be generated by the cooperative action of mast cell tryptase and neutrophil elastase (27). Thus, similar to complement degrad...
AbbreviationsHMWK, high molecular weight kininogen; SDS-PAGE, SDS-polyacrylamide gel electrophoresis. Keywords
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