Proteolysis of Human Thrombin Generates Novel Host Defense Peptides

PLoS Pathogens

Martin Malmsten¹  Artur Schmidtchen²  Anna Chalupka³  Praveen Papareddy³  Mukesh Pasupuleti³  Victoria Rydengård³  Matthias Mörgelin⁴  Björn Walse⁵ 

[1] Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland;Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden;Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden;Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden;SARomics AB, Lund, Sweden

关键词: Thrombin;    Pseudomonas aeruginosa;    Serine proteases;    Fibrin;    Neutrophils;    Blood plasma;    Staphylococcus aureus;    Bacteria;   

DOI  :  10.1371/journal.ppat.1000857

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The coagulation system is characterized by the sequential and highly localized activation of a series of serine proteases, culminating in the conversion of fibrinogen into fibrin, and formation of a fibrin clot. Here we show that C-terminal peptides of thrombin, a key enzyme in the coagulation cascade, constitute a novel class of host defense peptides, released upon proteolysis of thrombin in vitro, and detected in human wounds in vivo. Under physiological conditions, these peptides exert antimicrobial effects against Gram-positive and Gram-negative bacteria, mediated by membrane lysis, as well as immunomodulatory functions, by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, they are protective against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock. Moreover, the thrombin-derived peptides exhibit helical structures upon binding to lipopolysaccharide and can also permeabilize liposomes, features typical of “classical” helical antimicrobial peptides. These findings provide a novel link between the coagulation system and host-defense peptides, two fundamental biological systems activated in response to injury and microbial invasion.

【 授权许可】

CC BY