A 7-year-old unvaccinated boy from rural Uttar Pradesh presents with a 3-day history of sore throat, low-grade fever (38.2°C), and progressive dysphagia. On examination, he has a thick, greyish-white pseudomembrane covering the pharynx and tonsils that bleeds on attempted removal. Cervical lymph nodes are enlarged and tender. A throat swab is sent for culture. Which toxin produced by the causative organism is responsible for the systemic manifestations in this patient?

Explanation

## Pathophysiology of Diphtheria Toxin **Key Point:** Diphtheria toxin is an A–B toxin that catalyzes ADP-ribosylation of elongation factor 2 (EF-2), halting protein synthesis in host cells and causing systemic toxemia. ### Mechanism of Action Diphtheria toxin consists of: 1. **Fragment A (catalytic domain):** Catalyzes transfer of ADP-ribose from NAD^+^ to a modified histidine residue (diphthamide) on EF-2 2. **Fragment B (binding domain):** Binds to heparin-binding EGF-like growth factor (HB-EGF) receptor; enables endocytosis and translocation Inactivation of EF-2 → **complete halt of protein synthesis** → cell death, especially in myocardium, nervous system, and kidneys. ### Clinical Correlates | Manifestation | Mechanism | |---|---| | Pseudomembrane (local) | Tissue necrosis + fibrin deposition at infection site | | Myocarditis (systemic) | Toxin-mediated myocyte death; conduction blocks | | Peripheral neuropathy | Demyelination of cranial and peripheral nerves | | Respiratory paralysis | Diaphragmatic weakness from toxin diffusion | **Clinical Pearl:** The pseudomembrane is a **local manifestation** (bacterial overgrowth + tissue necrosis), but the life-threatening systemic complications (myocarditis, neuropathy) are entirely **toxin-mediated**, not due to invasive infection. This is why antitoxin (not antibiotics alone) is critical early in disease. **High-Yield:** Diphtheria toxin production is regulated by **iron availability** and the **β-phage lysogenic gene (tox)**. Only lysogenized strains carrying the tox gene produce toxin. Non-lysogenized C. diphtheriae strains cause only local infection without systemic toxemia. ### Why Diphtheria Toxin, Not Other Toxins? Lipopolysaccharide (LPS) is an endotoxin of Gram-negative bacteria; C. diphtheriae is Gram-positive and does not produce LPS. Streptococcal pyrogenic exotoxins and tetanospasmin are produced by different organisms (Streptococcus pyogenes and Clostridium tetani, respectively). [cite:Robbins 10e Ch 8]