Clostridium difficile Toxin Biology

Annu Rev Microbiol. 2017 Sep 8;71:281-307. doi: 10.1146/annurev-micro-090816-093458. Epub 2017 Jun 28.

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.

Keywords: ADP ribosylation; CDT; Clostridium difficile infection; Clostridium difficile toxins; Clostridium difficile transferase toxin; Rho proteins; actin; glucosylation; microtubules; toxin receptors; toxin uptake.

Publication types

  • Review

MeSH terms

  • ADP Ribose Transferases / metabolism
  • ADP Ribose Transferases / toxicity*
  • Animals
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / toxicity*
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / toxicity*
  • Clostridioides difficile / metabolism*
  • Cytoskeleton / drug effects
  • Endocytosis
  • Enterotoxins / metabolism
  • Enterotoxins / toxicity*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / physiology
  • Humans
  • Microtubules / drug effects
  • Virulence Factors / metabolism
  • Virulence Factors / toxicity*

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • Enterotoxins
  • Virulence Factors
  • tcdA protein, Clostridium difficile
  • toxB protein, Clostridium difficile
  • ADP Ribose Transferases
  • actin-specific ADP-ribosyltransferase, Clostridium