16.3: Diphtheria

Diphtheria is an acute, toxin-mediated infectious disease that primarily affects the upper respiratory tract. It is caused by Corynebacterium diphtheriae, a Gram-positive, pleomorphic rod that lacks spore-forming capability and exhibits a characteristic club-shaped morphology under microscopic examination. While C. diphtheriae can asymptomatically colonize mucosal surfaces, clinical disease manifests only when the bacterial strain is lysogenized by a specific β-corynephage. This phage integrates into the bacterial genome and enables the expression of the tox gene, which encodes diphtheria toxin—the major virulence determinant responsible for local tissue destruction and systemic complications. Immunization with the diphtheria toxoid vaccine induces neutralizing antibodies against the toxin, rather than the bacterium itself, and has dramatically reduced disease incidence worldwide.

Mechanism of Toxin Action

The virulence of C. diphtheriae is primarily mediated by diphtheria toxin, which disrupts host cellular processes through the following mechanism: The toxin is a single polypeptide chain composed of two functional subunits. Fragment B facilitates attachment to the host cell membrane by binding to the heparin-binding EGF-like growth factor receptor, while fragment A serves as the active enzymatic domain. Following receptor-mediated endocytosis, acidification within the endosome induces conformational changes that allow the translocation of fragment A into the cytoplasm. Once internalized, fragment A catalyzes the ADP-ribosylation of elongation factor 2 (EF-2), a key factor in the translocation step of protein synthesis, which utilizes GTP during its function. This post-translational modification irreversibly inactivates EF-2, effectively halting protein production and ultimately triggering cell death.

Pathological and Systemic Effects

The local effects of toxin-mediated cell death in the pharyngeal epithelium include necrosis, inflammation, and the accumulation of fibrin and cellular debris, culminating in the formation of a dense, adherent pseudomembrane. This membrane typically develops within a few days of symptom onset and can obstruct the airway, particularly in pediatric patients. If the exotoxin disseminates into the bloodstream, it may target distant organs, especially the myocardium and peripheral nerves. Myocarditis, a frequent and potentially fatal complication, can emerge within the first two weeks and may present with arrhythmias, conduction abnormalities, or heart block. Neurologic involvement may include cranial nerve palsies and polyneuropathy. Early administration of diphtheria antitoxin—which neutralizes unbound circulating toxin—remains the cornerstone of treatment and is most effective when given before extensive tissue binding occurs. Antibiotics are administered concurrently to eliminate the bacterial source. Long-term prevention relies on immunization with a diphtheria toxoid vaccine, which induces robust antibody-mediated protection against the toxin and has significantly reduced the global disease burden.