Fragmented tissue factor pathway inhibitor (TFPI) and TFPI C-terminal peptides eliminate serum-resistant Escherichia coli from blood cultures.
BACKGROUND
Tissue factor pathway inhibitor (TFPI) is a major regulator of blood clotting. Receipt of recombinant TFPI (rTFPI) protected animals from death in Escherichia coli-induced severe sepsis models and is under evaluation in a phase III clinical trial involving patients with severe community-acquired pneumonia. Because the mechanism of action of rTFPI in acute bacterial infection is not well understood, we sought to identify and map rTFPI peptides that have antimicrobial activity against E. coli.


METHODS
Fragmented rTFPI and C-terminal TFPI peptide activities against pathogenic E. coli strains were measured in ex vivo blood cultures and in serum.


RESULTS
The C-terminal peptides exhibited complement-dependent antibacterial activity and directly interacted with the bacterial cell surface of E. coli. Both complement-mediated killing and cell-surface binding were reversed by low amounts of heparin.


CONCLUSIONS
Our investigation revealed a previously unidentified mechanism of antibacterial activity for TFPI. C-terminal rTFPI fragments kill serum-resistant E. coli though the complement pathway of the innate immune system, suggesting a multimodal mechanism of action of rTFPI that may assist in reducing mortality in animal models of severe sepsis and contribute to therapeutic effectiveness.
Schirm
Sabine
S
Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.
Liu
Xu
X
Jennings
Lori L
LL
Jedrzejewski
Paul
P
Dai
Yumin
Y
Hardy
Stephen
S
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001769:Blood / Q000382:microbiology; D003171:Complement Pathway, Classical; D004926:Escherichia coli / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D008074:Lipoproteins; D010446:Peptide Fragments; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D010447:Peptide Hydrolases