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Human alpha-defensins inhibit Clostridium difficile toxin B

Torsten Giesemann1, Gregor Guttenberg, Klaus Aktories

  • 1Institut für Experimentelle and Klinische Pharmakologie und Toxikologie, Universität Freiburg, Freiburg, Germany.

Gastroenterology
|April 26, 2008
PubMed
Abstract

Insights

Human alpha-defensins inactivate Clostridium difficile toxin B, a key factor in severe diarrhea. These defensins may offer a natural defense against specific bacterial toxins by forming complexes and inhibiting enzyme activity.

Area of Science:

  • Microbiology
  • Immunology
  • Biochemistry

Background:

  • Clostridium difficile toxins A and B are critical virulence factors in pseudomembranous colitis and antibiotic-associated diarrhea.
  • These toxins function as glucosyltransferases, disrupting cellular signaling by inactivating Rho proteins.
  • Human alpha-defensins, part of the innate immune system, can neutralize various pathogens and bacterial exotoxins.

Purpose of the Study:

  • To investigate the inhibitory effects of alpha-defensins (HNP-1, HNP-3, HD-5) on the activity of Clostridium difficile toxins A and B.
  • To determine the mechanism and efficacy of alpha-defensin-mediated inactivation of C. difficile toxins.

Main Methods:

  • Assessed in vivo toxin inactivation using microscopy and CaCo-2 cell monolayer transepithelial resistance.
  • Analyzed Rac1 glucosylation in toxin-treated cells and in vitro glucosylation kinetics (K(m), IC(50)).
  • Studied defensin-toxin complex formation via precipitation and turbidity assays.

Main Results:

  • Human alpha-defensins reduced the cytotoxicity of C. difficile toxin B but not toxin A.
  • Alpha-defensins competitively inhibited toxin B-catalyzed glucosylation of Rho GTPases in vitro, increasing K(m) for UDP-glucose up to 10-fold.
  • The median inhibitory concentration (IC(50)) for alpha-defensins against toxin B glucosylation ranged from 0.6-1.5 micromol/L.

Conclusions:

  • Toxin B exhibits high-affinity interaction with human alpha-defensins.
  • Defensins represent a potential natural defense mechanism against clostridial glucosylating cytotoxins.

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