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MW: 308 kD
The four functional domains of Clostridium (today named Clostridioides) difficile toxin A (TcdA) include the glucosyltransferase domain (GTD) (red), auto-protease domain (APD) (blue), delivery domain (yellow), and combined repetitive oligo-peptides (CROPS) domain (gray).
Mileto et al. 2019 Microbiol Spectrum 7(3): GPP3- 0015-2018
Clostridium (today named Clostridioides) difficile toxin A (TcdA) is a member of the large clostridial glucosylating toxin family, members of which are also found in several other Pathogenic clostridia.
The C-terminal end of Clostridium (today named Clostridioides) difficile toxin A (TcdA), consisting of the combined repetitive oligo-peptides (CROPS) domain, is thought to facilitate receptor binding for the toxin.
CROPS-mediated receptor binding has been shown to increase Clostridium (today named Clostridioides) difficile toxin A (TcdA) - mediated cytotoxicity compared to a CROPS deletion mutant.
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Clostridioides (Clostridium) difficile toxins & Members
Clostridioides difficile is a bacterial pathogen that causes a range of clinical diseases, from mild to moderate diarrhea to more severe conditions such as pseudomembranous colitis and toxic megacolon (). The virulence of C. difficile is strain-dependent, with particularly virulent strains like the Hypervirulent Clade 2 (Luo et al. 2022 Cell 185: 980-994).
Several virulence factors have been identified, the most important of which are:
These toxins disrupt the Rho family of GTPases in host cells, leading to disease (Mileto et al. 2019 Microbiol Spectrum 7(3): GPP3- 0015-2018). TcdB is considered a dominant virulence factor (Luo et al. 2022 Cell 185: 980-994).
Clostridioides (Clostridium) difficile induces the expression of numerous transcripts associated with inflammation and extracellular matrix (ECM) degradation (). The toxin activity of C. difficile suppresses the Bacteroidaceae, which compete with C. difficile for amino acids (). Additionally, toxin-mediated degradation of collagen supports C. difficile growth in vitro ().
Clostridioides (Clostridium) difficile is part of the normal gut microbiota and is present in 2–5% of the adult population (). In the healthy human gut, its abundance is about 2.10% of all species (). It is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea (; Mileto et al. 2019 Microbiol Spectrum 7(3): GPP3- 0015-2018).
The conjugated primary bile acids taurocholate and taurochenodeoxycholate are powerful germinants for Clostridioides (Clostridium) difficile spores, with taurochenodeoxycholate being a weaker stimulant ().