What is the difference between C. diff toxin A and toxin B?

Differences Between C. difficile Toxin A and Toxin B

C. difficile toxin A and toxin B are distinct but related exotoxins that both contribute to C. difficile infection (CDI) pathogenesis, with toxin B being more essential for virulence while both toxins cause inflammation and tissue damage in the human intestine. 1, 2

Key Differences Between Toxin A and Toxin B

Structural and Functional Characteristics

• Toxin A (TcdA):

  • Larger molecule (308 kDa)
  • Primary role as an enterotoxin
  • Contains more repetitive sequences in its C-terminal region 1
  • Variation mainly occurs in the number of repeats in its C-terminal repetitive region 3

• Toxin B (TcdB):

  • Smaller molecule (270 kDa)
  • More potent cytotoxin (10-fold more cytotoxic than Toxin A)
  • Has undergone extensive homologous recombination throughout its entire sequence 3
  • Shows greater genetic diversity with 12 distinct subtypes (B1-B12) compared to 7 subtypes for Toxin A (A1-A7) 3

Pathogenic Importance

• Both toxins are pro-inflammatory and enterotoxic in human intestine 2
• Toxin B is considered more essential for C. difficile virulence:
  • Toxin A-negative/Toxin B-positive strains (A-B+) can cause clinically significant disease 4
  • Toxin B alone can induce intestinal epithelial cell damage, increase mucosal permeability, and stimulate inflammatory responses in human intestine 2

Diagnostic Implications

The distinction between these toxins has important diagnostic implications:

• Testing methods must detect both toxins since A-B+ strains are clinically relevant and increasingly common worldwide 4

• Diagnostic algorithms recommended by IDSA/SHEA guidelines include:

  • Nucleic Acid Amplification Tests (NAATs) for C. difficile toxin genes
  • Glutamate dehydrogenase (GDH) screening followed by toxin A/B enzyme immunoassays (EIA)
  • Two-step algorithms (GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) 5, 6

• EIA for toxin A/B is fast and inexpensive with high specificity but should not be used alone due to variable sensitivity (32-98%) 5, 6

Clinical Relevance

• Both toxins induce a cascade of cellular events resulting in:

  • Fluid secretion
  • Inflammation
  • Tissue damage 1

• Toxin detection is crucial for CDI diagnosis:

  • Testing should only be performed on unformed stools 5
  • Repeat testing within 7 days during the same episode of diarrhea is not recommended 5

Antigenic Properties

• Toxins A and B share at least one common epitope, suggesting they have a common subunit 7
• The diversity in TcdB has led to binary functional and antigenic groups that affect:
  • Cell-rounding phenotypes
  • Receptor recognition patterns
  • Neutralization efficiency by therapeutic antibodies like bezlotoxumab 3

Treatment Considerations

The understanding of toxin structure and function has implications for treatment:

• Standard treatment for CDI includes oral vancomycin or fidaxomicin 6
• Therapeutic strategies and vaccines need to target both toxins for effective treatment 2
• Eight universally conserved surface patches across the TcdB structure have been identified as potential targets for broad-spectrum therapeutics 3

Understanding the differences between C. difficile toxin A and toxin B is essential for accurate diagnosis, effective treatment, and development of targeted therapeutics for C. difficile infection.