Question
Pathogenesis of diphtheria
Answer
Pathogenesis of diphtheria (caused by toxigenic Corynebacterium diphtheriae):
The organism is transmitted by droplet infection and colonizes the pharyngeal/tonsillar mucosa (or occasionally skin, in cutaneous diphtheria) without invading deeper tissue — it remains a local, non-invasive infection, with all systemic effects mediated entirely by the exotoxin it produces.
Toxin production: only strains lysogenized by a bacteriophage carrying the tox gene (phage/lysogenic conversion) produce diphtheria toxin; non-lysogenized strains are non-toxigenic and cause, at most, mild local disease.
Toxin mechanism: diphtheria toxin is an AB-type exotoxin — the B subunit binds to a specific host cell receptor (heparin-binding EGF-like growth factor) and mediates entry of the A subunit into the cytoplasm, where it ADP-ribosylates and inactivates Elongation Factor-2 (EF-2), a protein essential for ribosomal translocation during protein synthesis — this halts host cell protein synthesis, causing cell death. The toxin has a particular affinity for tissues with high protein turnover, notably cardiac muscle (causing myocarditis) and peripheral nerves/Schwann cells (causing demyelination and neuropathy, e.g., palatal palsy, later limb paralysis).
Local effects: the resulting local tissue necrosis, combined with fibrin exudate, dead epithelial cells, and inflammatory cells, forms the characteristic grey-white, adherent pseudomembrane over the tonsils/pharynx, which bleeds if forcibly removed; extension of the membrane can cause mechanical airway obstruction (“diphtheritic croup”).
Systemic effects: absorbed toxin disseminates via blood/lymphatics to distant organs, producing the characteristic complications of myocarditis (the most serious, often fatal complication) and peripheral/cranial neuropathy, independent of the primary local infection site.