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.
Highlights
Most virulent strains of Clostridioides difficile produce two large single unit toxins which act via glycosylation of small GTP-binding proteins involved in cell cytoskeleton organization resulting in the disruption of epithelial tight junctions [1,2,3]
From 1 September, 1999 to 1 January, 2002, 10,668 stools were submitted for C. difspecimens, C. difficile culture and TcdA enzyme immunoassays (EIA) were positive in 1436
From September 1999 to January 2002, TcdA−/B+ variants accounted for 1.6% of all the recovered C. difficile isolates within a single healthcare system in United States
Summary
Most virulent strains of Clostridioides difficile produce two large single unit toxins which act via glycosylation of small GTP-binding proteins involved in cell cytoskeleton organization resulting in the disruption of epithelial tight junctions [1,2,3]. In the late 1990s, many clinical laboratories implemented TcdA enzyme immunoassays (EIA) for C. difficile testing in place of cytotoxin assays because of the rapidity and simplicity of the test, as well as initial data showing comparable results with cell culture assays [7,8]. These EIAs employed a monoclonal antibody (PCG-4) that recognizes epitopes encoded by a region of highly repetitive DNA sequences in the 30 end of tcdA [9].
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