Human a-Defensin-5 efficiently neutralizes clostridioides difficile toxins TcdA, TcdB, and CDT
Wissenschaftlicher Artikel
Authors
Korbmacher, Michael
Fischer, Stephan
Landberger, Marc
Papatheodorou, Panagiotis
Aktories, Klaus
Institutions
UKU. Institut für Pharmakologie und ToxikologieExternal cooperations
Albert-Ludwigs-Universität FreiburgPublished in
Frontiers in Pharmacology ; 11 (2020). - Art.-Nr. 1204. - eISSN 1663-9812
Link to original publication
https://dx.doi.org/10.3389%2Ffphar.2020.01204Peer review
ja
Document version
publishedVersion
Abstract
Infections with the pathogenic bacterium Clostridioides (C.) difficile are coming more into focus, in articular in hospitalized patients after antibiotic treatment. C. difficile produces the exotoxins TcdA and TcdB. Since some years, hypervirulent strains are described, which produce in addition the binary actin ADP-ribosylating toxin CDT. These strains are associated with more severe clinical presentations and increased morbidity and frequency. Once in the cytosol of their target cells, the catalytic domains of TcdA and TcdB glucosylate and thereby inactivate small Rho-GTPases whereas the enzyme subunit of CDT ADP-ribosylates G-actin. Thus, enzymatic activity of the toxins leads to destruction of the cytoskeleton and breakdown of the epidermal gut barrier integrity. This causes clinical symptoms ranging from mild diarrhea to life-threatening pseudomembranous colitis. Therefore, pharmacological inhibition of the secreted toxins is of peculiar medical interest. Here, we investigated the neutralizing effect of the human antimicrobial peptide α-defensin-5 toward TcdA, TcdB, and CDT in human cells. The toxin-neutralizing effects of α-defensin-5 toward TcdA, TcdB, and CDT as well as their medically relevant combination were demonstrated by analyzing toxins-induced changes in cell morphology, intracellular substrate modification, and decrease of trans-epithelial electrical resistance. For TcdA, the underlying mode of inhibition is most likely based on the formation of inactive toxin-defensin-aggregates whereas for CDT, the binding- and transport-component might be influenced. The application of α-defensin-5 delayed intoxication of cells in a time- and concentration-dependent manner. Due to its effect on the toxins, α-defensin-5 should be considered as a candidate to treat severe C. difficile–associated diseases.
Funding information
DFG Biohybridtransporter zum zellspezifischen Transport und der kontrollierten Freisetzung von pharmakologisch aktiven Peptiden (C02) / DFG [316249678]
Gefördert vom Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
Gefördert vom Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
Subject Headings
Clostridium difficile [GND]Toxin [GND]
Clostridium infections [MeSH]
Bacterial toxins [MeSH]
Bacterial proteins [MeSH]
Exotoxins [MeSH]
Keywords
C. difficile infection; large clostridial glucosylating toxins; binary actin ADP-ribosylating toxin; toxin inhibitor; AB-type protein toxinsDewey Decimal Group
DDC 610 / Medicine & healthMetadata
Show full item recordCitation example
Korbmacher, Michael et al. (2020): Human a-Defensin-5 efficiently neutralizes clostridioides difficile toxins TcdA, TcdB, and CDT. Open Access Repositorium der Universität Ulm. http://dx.doi.org/10.18725/OPARU-33922
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