The TFPI-2 Derived Peptide EDC34 Improves Outcome of Gram-Negative Sepsis

PLoS Pathogens

Martin Malmsten¹  Martina Kalle²  Praveen Papareddy²  Artur Schmidtchen²  Ole E. Sørensen³  Matthias Mörgelin³ 

[1] Department of Pharmacy, Uppsala University, 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

关键词: Blood plasma;    Pseudomonas aeruginosa;    Mouse models;    Blood;    Cytokines;    Complement system;    Complement activation;    Escherichia coli infections;   

DOI  :  10.1371/journal.ppat.1003803

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections.

【 授权许可】

CC BY