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Human peptide α‐defensin‐1 interferes with Clostridioides difficile toxins TcdA, TcdB, and CDT
Author(s) -
Fischer Stephan,
Ückert AnnaKatharina,
Landenberger Marc,
Papatheodorou Panagiotis,
HoffmannRichter Carola,
Mittler AnnKatrin,
Ziener Ulrich,
Hägele Marlen,
Schwan Carsten,
Müller Martin,
Kleger Alexander,
Benz Roland,
Popoff Michel R.,
Aktories Klaus,
Barth Holger
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902816r
Subject(s) - defensin , clostridium difficile toxin b , microbiology and biotechnology , clostridium difficile toxin a , pseudomembranous colitis , biology , toxin , caco 2 , colitis , in vivo , in vitro , immunology , clostridium difficile , biochemistry , antibiotics , antimicrobial
The human pathogenic bacterium Clostridioides difficile produces two exotoxins TcdA and TcdB, which inactivate Rho GTPases thereby causing C. difficile ‐associated diseases (CDAD) including life‐threatening pseudomembranous colitis. Hypervirulent strains produce additionally the binary actin ADP‐ribosylating toxin CDT. These strains are hallmarked by more severe forms of CDAD and increased frequency and severity. Once in the cytosol, the toxins act as enzymes resulting in the typical clinical symptoms. Therefore, targeting and inactivation of the released toxins are of peculiar interest. Prompted by earlier findings that human α‐defensin‐1 neutralizes TcdB, we investigated the effects of the defensin on all three C. difficile toxins. Inhibition of TcdA, TcdB, and CDT was demonstrated by analyzing toxin‐induced changes in cell morphology, substrate modification, and decrease in transepithelial electrical resistance. Application of α‐defensin‐1 protected cells and human intestinal organoids from the cytotoxic effects of TcdA, TcdB, CDT, and their combination which is attributed to a direct interaction between the toxins and α‐defensin‐1. In mice, the application of α‐defensin‐1 reduced the TcdA‐induced damage of intestinal loops in vivo. In conclusion, human α‐defensin‐1 is a specific and potent inhibitor of the C. difficile toxins and a promising agent to develop novel therapeutic options against C. difficile infections.