Clostridioides difficile, commonly known as C. diff, is a bacterium that can cause severe diarrheal illness in humans. It causes disease primarily through potent toxins. Specifically, Toxin A (TcdA) and Toxin B (TcdB) are recognized as the main factors contributing to the virulence of C. diff infections. These toxins disrupt the intestinal lining, leading to characteristic symptoms.
Toxin A: Its Actions and Impact
Toxin A (TcdA) is an enterotoxin, primarily affecting the intestines and causing fluid secretion. Its molecular action involves entering host cells and then modifying small proteins called Rho GTPases, such as Rho, Rac, and Cdc42. This modification, glucosylation, involves adding a glucose molecule to these proteins, which inactivates them.
The inactivation of Rho GTPases by Toxin A leads to the disruption of the actin cytoskeleton, the internal scaffolding that gives cells their shape and allows them to move. Tight junctions between cells, which maintain the intestinal barrier, become compromised, leading to increased permeability and fluid leakage into the intestines. Toxin A also contributes to inflammation and damage to the intestinal lining, attracting immune cells like neutrophils to the affected area.
Toxin B: Its Actions and Impact
Toxin B (TcdB) is a cytotoxin, causing direct cell damage and death. Like Toxin A, Toxin B also targets and inactivates Rho GTPases through glucosylation, leading to disruption of the cell’s internal cytoskeleton. This action results in rapid cell rounding and ultimately cell death, often within hours of exposure.
Toxin B enters host cells via receptor-mediated endocytosis, binding to specific surface receptors. Once inside, the acidic environment of the endosome triggers a change in the toxin’s shape, allowing it to form pores in the endosomal membrane. This pore formation allows the toxin to enter the cytosol, where it inactivates Rho GTPases. Toxin B is a potent inducer of inflammation and significant mucosal damage within the colon.
Comparing Toxin A and Toxin B
Toxin A and Toxin B are large clostridial toxins, both belonging to the glucosylating toxin family. They possess similar structural domains, including a glucosyltransferase domain responsible for their enzymatic activity, a delivery domain, and a receptor-binding domain. Both toxins target Rho GTPases, small proteins regulating cell scaffolding, leading to cell rounding and intestinal barrier disruption.
Despite these commonalities, Toxin B is generally considered more potent than Toxin A in cell culture studies, often exhibiting 4-fold to 200-fold higher cytotoxic activity. While Toxin A was traditionally viewed as an enterotoxin primarily causing fluid secretion and inflammation, and Toxin B as a cytotoxin causing direct cell death, both toxins can exhibit aspects of both properties. They are encoded by distinct genes, tcdA and tcdB, located within the pathogenicity locus of the C. difficile genome. Historically, Toxin A was believed to be the main driver of disease, but current understanding emphasizes Toxin B as the major virulence factor, with some disease-causing strains producing only Toxin B.
Clinical Significance of Toxin Types
Understanding the distinction between Toxin A and Toxin B is important for clinical management of C. difficile infection. The presence of either or both toxins in stool samples is a crucial factor for diagnosing C. difficile infection. Detecting Toxin B, in particular, is often the primary target in diagnostic assays due to its recognized role as a major virulence factor.
Some C. difficile strains produce only Toxin B but still cause severe disease, highlighting its significant role. While rapid enzyme immunoassays can detect Toxin A, Toxin B, or both, their sensitivity can be a concern. Specimens should be tested promptly or refrigerated to prevent toxin degradation. Advanced molecular tests like PCR are highly sensitive for detecting the toxin-producing C. difficile organism, but a positive result does not always indicate active disease.