The Relative Role of Toxins A and B in the Virulence of Clotridioides difficile

Abstract

Most pathogenic strains of C. difficile possess two large molecular weight single unit toxins with four similar functional domains. The toxins disrupt the actin cytoskeleton of intestinal epithelial cells leading to loss of tight junctions, which ultimately manifests as diarrhea in the host. While initial studies of purified toxins in animal models pointed to toxin A (TcdA) as the main virulence factor, animal studies using isogenic mutants demonstrated that toxin B (TcdB) alone was sufficient to cause disease. In addition, the natural occurrence of TcdA−/TcdB+ (TcdA−/B+)mutant strains was shown to be responsible for cases of C. difficile infection (CDI) with symptoms identical to CDI caused by fully toxigenic (A+/B+) strains. Identification of these cases was delayed during the period when clinical laboratories were using immunoassays that only detected TcdA (toxA EIA). Our hospital laboratory at the time performed culture as well as toxA EIA on patient stool samples. A total of 1.6% (23/1436) of all clinical isolates recovered over a 2.5-year period were TcdA−/B+ variants, the majority of which belonged to the restriction endonuclease analysis (REA) group CF and toxinotype VIII. Despite reports of serious disease due to TcdA−/B+ CF strains, these infections were typically mild, often not requiring specific treatment. While TcdB alone may be sufficient to cause disease, clinical evidence suggests that both toxins have a role in disease.

Clostridioides difficile Infection among Cirrhotic Patients with Variceal Bleeding

“…However, the healthcare systems are all aware of this potential threat, as CDI should have been discussed at a rather global scale since it has also shifted to community onset [ 14 ]. The environment stands as a high-ground factor in disease evolution, namely because of asymptomatic colonization as well as spore-resistant circumstances within medical care systems, which will eventually lead to new virulent strains [ 15 ]. Thus, first focusing on a targeted group of patients who require specific antibiotics might help restrain morbidity and health costs and enable new approaches to prevent widespread infection.…”

Protective Effects of Alginate and Chitosan Oligosaccharides against Clostridioides difficile Bacteria and Toxin

“…TcdA and TcdB are the major virulence factors of C. difficile and belong to the family of large clostridial glucosylating toxins [7,8]. Both TcdA and TcdB are large, single-unit toxins that act via the mono-glycosylation of small GTP-binding proteins involved in the organization of cytoskeletal dynamics, and their combined action results in colonic tissue inflammation and massive colonic fluid secretion, i.e., watery diarrhea [9,10]. Glycosylation of Rho (Rho, Rac, and Cdc42) proteins halts their interaction with downstream effectors and blocks Rho-dependent signaling pathways, thus causing cytopathic and cytotoxic effects.…”

Repurposing epigenetic inhibitors to target the Clostridioides difficile-specific DNA adenine methyltransferase and sporulation regulator CamA

“…C. difficile infections are seen predominantly in people who have had both recent medical care (due to in-hospital exposure) and antibiotic treatment (due to suppression of the normal colon bacteria) [ 19 ]. This Gram-positive pathogen produces endospores, making decontamination difficult [ 20 , 21 ], and it causes substantial tissue damage by producing significant toxins [ 22 , 23 ]. It prolongs its presence by stabilizing the colon bacterial population (microbiota, or microbiome) in an unhealthy distribution [ 24 , 25 ].…”