Clostridium difficile Toxin Biology

Abstract

Clostridium difficile is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins: C. difficile toxins A (TcdA) and B (TcdB), and C. difficile transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell membrane receptors and are internalized. The N-terminal glucosyltransferase and autoprotease domains of the toxins translocate from low-pH endosomes into the cytosol. After activation by inositol hexakisphosphate (InsP6), the autoprotease cleaves and releases the glucosyltransferase domain into the cytosol, where GTP-binding proteins of the Rho/Ras family are mono-O-glucosylated and, thereby, inactivated. Inactivation of Rho proteins disturbs the organization of the cytoskeleton and affects multiple Rho-dependent cellular processes, including loss of epithelial barrier functions, induction of apoptosis, and inflammation. CDT, the third C. difficile toxin, is a binary actin-ADP-ribosylating toxin that causes depolymerization of actin, thereby inducing formation of the microtubule-based protrusions. Recent progress in understanding of the toxins' actions include insights into the toxin structures, their interaction with host cells, and functional consequences of their actions.

Early cell death induced by Clostridium difficile TcdB: Uptake and Rac1-glucosylation kinetics are decisive for cell fate

“…These two protein toxins mediate their cell entry by receptor‐based endocytosis which exploits clathrin‐ and/or dynamin‐dependent pathways. (Aktories, Schwan, & Jank, ; Chandrasekaran, Kenworthy, & Lacy, ; Gerhard, Frenzel, Goy, & Olling, ; Papatheodorou, Zamboglou, Genisyuerek, Guttenberg, & Aktories, ). Both toxins, TcdA and TcdB, escape early endosomes by insertion into the vesicular membrane and by translocation of at least the N‐terminal GT domain (GTD) through a pore built in the vesicular membrane (Giesemann et al, ).…”

Pathogenic Puppetry: Manipulation of the Host Actin Cytoskeleton by Chlamydia trachomatis

“…The chlamydial toxin CT166 has also been proposed to indirectly mediate actin depolymerization, acting as an inhibitor of host actin-polymerizing factors. CT166 contains a DXD amino acid motif with homology to the Clostridium difficile toxin TcdB, a glucosylator of the Rho-family GTPases Rac1 and Cdc42 (both well-known regulators of actin polymerization) [104,105]. Glucosylation of Rac1/Cdc42 by TcdB is inhibitory and irreversible, occurring at a catalytic threonine residue essential for GTP binding [105].…”

“…CT166 contains a DXD amino acid motif with homology to the Clostridium difficile toxin TcdB, a glucosylator of the Rho-family GTPases Rac1 and Cdc42 (both well-known regulators of actin polymerization) [104,105]. Glucosylation of Rac1/Cdc42 by TcdB is inhibitory and irreversible, occurring at a catalytic threonine residue essential for GTP binding [105]. The downstream effect of TcdB activity is a dramatic redistribution of filamentous actin, resulting in cell shrinking, the loss of stress fibers, and host cell death [105,106].…”

Vegetative Cell and Spore Proteomes ofClostridioides difficileshow finite differences and reveal potential biomarkers.

“…This necessitates designing strategies and algorithms to optimize the diagnostic tools (2). Pathogenesis of CDI is manifested via its Rho-glycosylating toxins TcdA and TcdB (3). Moreover, in response to adverse conditions, C. difficile can form endospores - multi-layered, highly resistant cellular entities - that are the main transmissible forms (4) in C. difficile infections.…”