title: The TFPI-2 derived peptide EDC34 improves outcome of gram-negative sepsis.
abstract: 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.
authors: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors: Praveen
authors: P
authors: Papareddy
authors: Martina
authors: M
authors: Kalle
authors: Ole E
authors: OE
authors: Sørensen
authors: Martin
authors: M
authors: Malmsten
authors: Matthias
authors: M
authors: Mörgelin
authors: Artur
authors: A
authors: Schmidtchen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004927:Escherichia coli Infections / Q000188:drug therapy; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D018805:Sepsis / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; C000591220:EDC34 peptide; D006023:Glycoproteins; D010446:Peptide Fragments; C021240:tissue-factor-pathway inhibitor 2