PUBLICATION
Human α-Defensin-6 Neutralizes Clostridioides difficile Toxins TcdA and TcdB by Direct Binding
- Authors
- Barthold, L., Heber, S., Schmidt, C.Q., Gradl, M., Weidinger, G., Barth, H., Fischer, S.
- ID
- ZDB-PUB-220515-4
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(9): (Journal)
- Registered Authors
- Gradl, Marion, Weidinger, Gilbert
- Keywords
- Clostridioides difficile infections, bacterial AB-type protein toxins, human antimicrobial peptide, large clostridial glucosylating toxins TcdA and TcdB, toxin inhibitor, zebrafish, α-defensin-6
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/pharmacology
- Antibodies, Bacterial
- Bacterial Proteins/metabolism
- Bacterial Toxins*/metabolism
- Clostridioides difficile*
- Clostridium Infections*/microbiology
- Enterotoxins/chemistry
- Humans
- Zebrafish/metabolism
- alpha-Defensins*/pharmacology
- rho GTP-Binding Proteins/metabolism
- PubMed
- 35562899 Full text @ Int. J. Mol. Sci.
Citation
Barthold, L., Heber, S., Schmidt, C.Q., Gradl, M., Weidinger, G., Barth, H., Fischer, S. (2022) Human α-Defensin-6 Neutralizes Clostridioides difficile Toxins TcdA and TcdB by Direct Binding. International Journal of Molecular Sciences. 23(9):.
Abstract
Rising incidences and mortalities have drawn attention to Clostridioides difficile infections (CDIs) in recent years. The main virulence factors of this bacterium are the exotoxins TcdA and TcdB, which glucosylate Rho-GTPases and thereby inhibit Rho/actin-mediated processes in cells. This results in cell rounding, gut barrier disruption and characteristic clinical symptoms. So far, treatment of CDIs is limited and mainly restricted to some antibiotics, often leading to a vicious circle of antibiotic-induced disease recurrence. Here, we demonstrate the protective effect of the human antimicrobial peptide α-defensin-6 against TcdA, TcdB and the combination of both toxins in vitro and in vivo and unravel the underlying molecular mechanism. The defensin prevented toxin-mediated glucosylation of Rho-GTPases in cells and protected human cells, model epithelial barriers as well as zebrafish embryos from toxic effects. In vitro analyses revealed direct binding to TcdB in an SPR approach and the rapid formation of TcdB/α-defensin-6 complexes, as analyzed with fluorescent TcdB by time-lapse microscopy. In conclusion, the results imply that α-defensin-6 rapidly sequesters the toxin into complexes, which prevents its cytotoxic activity. These findings extend the understanding of how human peptides neutralize bacterial protein toxins and might be a starting point for the development of novel therapeutic options against CDIs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping