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Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Concentration- and pH-Dependent Oligomerization of the Thrombin-Derived C-Terminal Peptide TCP-25

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. A C-terminal peptide of TFPI-1 facilitates cytosolic delivery of nucleic acid cargo into mammalian cells

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. A dual-action peptide-containing hydrogel targets wound infection and inflammation

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Degradable dendritic nanogels as carriers for antimicrobial peptides

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Jitka Petrlova
  • Ganna Petruk
  • Roland G Huber
  • Eilish W McBurnie
  • Mariena J A van der Plas
  • Peter J Bond
  • Manoj Puthia
  • Artur Schmidtchen
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Thrombin-derived C-terminal peptides (TCPs), including a major 11-kDa fragment (TCP96), are produced through cleavage by human neutrophil elastase and aggregate lipopolysaccharide (LPS) and the Gram-negative bacterium Escherichia coli However, the physiological roles of TCP96 in controlling bacterial infections and reducing LPS-induced inflammation are unclear. Here, using various biophysical methods, in silico molecular modeling, microbiological and cellular assays, and animal models, we examined the structural features and functional roles of recombinant TCP96 (rTCP96) in the aggregation of multiple bacteria and the Toll-like receptor (TLR) agonists they produce. We found that rTCP96 aggregates both Gram-negative and Gram-positive bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and their cell-wall components LPS, lipid A, and lipoteichoic acid (LTA). The Gram-negative bacteria E. coli and P. aeruginosa were particularly sensitive to aggregation-induced bacterial permeabilization and killing. As a proof of concept, we show that rTCP96 reduces LPS-induced NF-κB activation in human monocytes, as well as in mouse models of LPS-induced subcutaneous inflammation. Moreover, in a mouse model of subcutaneous inoculation with P. aeruginosa, rTCP96 reduced bacterial levels. Together, these results link TCP-mediated aggregation of endotoxins and bacteria in vitro to attenuation of inflammation and bacterial levels in vivo.

Original languageEnglish
JournalJournal of Biological Chemistry
Volume295
Issue number11
Pages (from-to)3417-3430
Number of pages14
ISSN0021-9258
DOIs
Publication statusPublished - 13 Mar 2020

    Research areas

  • Animals, Anti-Bacterial Agents/pharmacology, Computer Simulation, Gram-Negative Bacteria/drug effects, Gram-Positive Bacteria/drug effects, Humans, Inflammation/pathology, Ligands, Lipopolysaccharides/chemistry, Male, Mice, Inbred BALB C, Microbial Sensitivity Tests, Microbial Viability/drug effects, Monocytes/drug effects, Protein Aggregates, Proteolysis, Recombinant Proteins/pharmacology, THP-1 Cells, Teichoic Acids/chemistry, Thrombin/pharmacology, Toll-Like Receptors/metabolism

ID: 61844636