Novel Endogenous Antimicrobial Peptides
Sammanfattning: Antimicrobial peptides serve as a first line of defence against invading microorganisms and are an essential part of our fast innate immune system. They are ancient molecules found in all classes of life. Antimicrobial peptides rapidly kill a broad spectrum of microbes and are immunomodulatory, i.e. having additional actions influencing inflammation and other innate immune responses. Results presented in this thesis demonstrate that proteases of common human pathogens degrade and inactivate the antimicrobial peptide LL-37, probably a strategy for bacteria to circumvent the action of antimicrobial peptides. Likewise, heavily sulphated glycosaminoglycans like dermatan sulphate and heparin were shown to bind to and inactivate LL-37. Furthermore, we demonstrate that structural characteristics associated with heparin affinity (cationicity and amphipathicity) may confer antimicrobial properties to any given peptide. Heparin-binding consensus sequences were proven to be active against Gram-positive bacteria, Gram-negative bacteria and the fungus Candida albicans. Similar results were obtained with synthetic peptides derived from heparin-binding sequences within endogenous proteins. In addition, novel antimicrobial activity and heparin-binding capacity were discovered for the anaphylatoxin C3a, generated during activation of the complement system, and the inactive derivative of C3a (C3adesArg), as well as shorter synthetic peptides from the molecule. Novel antimicrobial activity was also shown for the heparin binding and cell-binding domain 5 of high molecular weight kininogen, a substrate in the intrinsic pathway of coagulation. Interestingly, the peptide HKH20 (His479 His498) from this domain was active in high salt, and highly resistant to degradation by various bacterial proteases. The understanding that heparin binding is a property of many antimicrobial peptides may represent a powerful tool in the discovery of novel endogenous antimicrobial peptides from complex biological mixtures.
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