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- Title
Human neutrophils are activated by a peptide fragment of C lostridium difficile toxin B presumably via formyl peptide receptor.
- Authors
Goy, Sebastian D.; Olling, Alexandra; Neumann, Detlef; Pich, Andreas; Gerhard, Ralf
- Abstract
C lostridium difficile may induce antibiotic-associated diarrhoea and, in severe cases, pseudomembranous colitis characterized by tremendous neutrophil infiltration. All symptoms are caused by two exotoxins: TcdA and TcdB. We describe here the activation of isolated human blood neutrophils by TcdB and, moreover, by toxin fragments generated by limited proteolytical digestion. Kinetics and profiles of TcdB-induced rise in intracellular-free Ca2+ and reactive oxygen species production were similar to that induced by fMLF, which activates the formyl peptide receptor ( FPR) recognizing formylated bacterial peptide sequences. Transfection assays with the FPR-1 isoform hFPR26 in HEK293 cells, heterologous desensitization experiments and FPR inhibition via cyclosporine H strongly suggest activation of cells via FPR-1. Domain analyses revealed that the N-terminal glucosyltransferase domain of TcdB is a potent activator of FPR pointing towards an additional mechanism that might contribute to pathogenesis. This pro-inflammatory ligand effect can be triggered even by cleaved and, thus, non-cytotoxic toxin. In summary, we report (i) a ligand effect on neutrophils as completely new molecular mode of action, (ii) pathogenic potential of truncated or proteolytically cleaved 'non-cytotoxic' fragments and (iii) an interaction of the N-terminal glucosyltransferase domain instead of the C-terminal receptor binding domain of TcdB with target cells.
- Subjects
NEUTROPHILS; CLOSTRIDIOIDES difficile; FORMYL peptide receptors; ANTIBIOTICS; PSEUDOMEMBRANOUS enterocolitis; SYMPTOMS; REACTIVE oxygen species
- Publication
Cellular Microbiology, 2015, Vol 17, Issue 6, p893
- ISSN
1462-5814
- Publication type
Article
- DOI
10.1111/cmi.12410