Human alpha-defensin-1 protects cells from intoxication with Clostridium perfringens iota toxin

摘要

Iota toxin is produced by Clostridium perfringens type E strains and associated with diarrhea in cattle and lambs. This binary protein toxin comprises the enzyme component iota a (Ia), which ADP-ribosylates G-actin, and the separate transport component iota b (Ib), which delivers Ia into the cytosol of target cells. Ib binds to cell receptors and forms biologically active toxin complexes with Ia, which cause rounding of adherent cells due to the destruction of the actin cytoskeleton. Here, we report that the human peptide alpha-defensin-1 protects cultured cells including human colon cells from intoxication with iota toxin. In contrast, the related beta-defensin-1 had no effect, indicating a specific mode of action. The alpha-defensin-1 did not inhibit ADP-ribosylation of actin by Ia in vitro. Pretreatment of Ib with alpha-defensin-1 prior to addition of Ia prevented intoxication. Additionally, alpha-defensin-1 protected cells from cytotoxic effects mediated by Ib in the absence of Ia, implicating that alpha-defensin-1 interacts with Ib to prevent the formation of biologically active iota toxin on cells. In conclusion, the findings contribute to a better understanding of the functions of alpha-defensin-1 and suggest that this human peptide might be an attractive starting point to develop novel pharmacological options to treat/prevent diseases associated with iota toxin-producing Clostridium perfringens strains.