Abstract
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by production of the Rho GTPase-glucosylating toxins A and B. Recently emerging hypervirulent Clostridium difficile strains additionally produce the binary ADP-ribosyltransferase toxin CDT (Clostridium difficile transferase), which ADP-ribosylates actin and inhibits actin polymerization. Thus far, the role of CDT as a virulence factor is not understood. Here we report by using time-lapse- and immunofluorescence microscopy that CDT and other binary actin-ADP-ribosylating toxins, including Clostridium botulinum C2 toxin and Clostridium perfringens iota toxin, induce redistribution of microtubules and formation of long (up to >150 µm) microtubule-based protrusions at the surface of intestinal epithelial cells. The toxins increase the length of decoration of microtubule plus-ends by EB1/3, CLIP-170 and CLIP-115 proteins and cause redistribution of the capture proteins CLASP2 and ACF7 from microtubules at the cell cortex into the cell interior. The CDT-induced microtubule protrusions form a dense meshwork at the cell surface, which wrap and embed bacterial cells, thereby largely increasing the adherence of Clostridia. The study describes a novel type of microtubule structure caused by less efficient microtubule capture and offers a new perspective for the pathogenetic role of CDT and other binary actin-ADP-ribosylating toxins in host–pathogen interactions.
Highlights
Many bacterial protein toxins affect the actin cytoskeleton by modulating the activity of Rho GTPases, including RhoA, Rac and Cdc42 [1]
C. difficile transferase (CDT) belongs to the family of binary actin-ADP-ribosylating toxins [12,13], which are produced by various pathogenic species of the genus Clostridium and Bacillus, including C. botulinum (C2 toxin), C. perfringens, C. spiroforme (C. spiroforme toxin, CST) and B. cereus [1,14]
Our findings show a novel type of microtubule structures induced by actin-ADP-ribosylating toxins and propose an important role of these toxins in host– pathogen interactions by their effects on adherence and colonization of Clostridia
Summary
Many bacterial protein toxins affect the actin cytoskeleton by modulating the activity of Rho GTPases, including RhoA, Rac and Cdc42 [1] Prototypic examples of these toxins are Clostridium difficile toxins A and B, which cause antibiotic-associated diarrhea and pseudomembranous colitis [2,3,4,5]. CDT belongs to the family of binary actin-ADP-ribosylating toxins [12,13], which are produced by various pathogenic species of the genus Clostridium and Bacillus, including C. botulinum (C2 toxin), C. perfringens (iota toxin), C. spiroforme (C. spiroforme toxin, CST) and B. cereus (vegetative insecticidal proteins, VIP) [1,14]. These toxins consist of a biologically active, actin-modifying ADPribosyltransferase and a separated binding component, which is involved in binding and transport of the enzyme component into the cytosol of target cells
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