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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Degradable dendritic nanogels as carriers for antimicrobial peptides

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind295
Udgave nummer11
Sider (fra-til)3417-3430
Antal sider14
ISSN0021-9258
DOI
StatusUdgivet - 13 mar. 2020

Bibliografisk note

© 2020 Petrlova et al.

ID: 61844636