Pathogenesis and Clinical manifestations of Corynebacterium diphtheriae

Pathogenesis of Corynebacterium diphtheriae

  • In nature, C diphtheriae occurs in the respiratory tract, in wounds, or on the skin of infected persons or normal carriers.
  • It is spread by droplets or by contact to susceptible individuals; the bacilli then grow on mucous membranes or in skin abrasions, and those that are toxigenic start producing toxin.
  • Diphtheria toxin is the major virulence factor of C. diphtheria and is a heat-labile, single-chain, three domain polypeptide (62 kDa) that can be lethal in a dose of 0.1 μg/kg body weight.
  • The tox gene that codes for the exotoxin is introduced into strains of C. diphtheriae by a lysogenic bacteriophage, β-phage.
  • Two processing steps are necessary for the active gene product to be secreted: (1) proteolytic cleavage of the leader sequence from the Tox protein during secretion from the bacterial cell and (2) cleavage of the toxin molecule into two polypeptides (A and B) that remain attached by a disulfide bond.
  • Three functional regions exist on the toxin molecule: a catalytic region on the A subunit and a receptor-binding region and a translocation region on the B subunit.
  • The receptor for the toxin is heparin-binding epidermal growth factor, which is present on the surface of many eukaryotic cells, particularly heart and nerve cell.
  • The binding of the receptor domain to host cell membrane proteins CD-9 and heparin-binding epidermal growth factor (HB-EGF) triggers the entry of the toxin into the cell through receptor-mediated endocytosis.

Pathogenesis and Clinical manifestations of Corynebacterium diphtheriae

  • Acidification of the translocation domain within a developing endosome leads to creation of a protein channel that facilitates movement of Fragment A into the host cell cytoplasm.
  • The A subunit then terminates host cell protein synthesis by inactivating elongation factor-2 (EF-2) which is required for translocation of polypeptidyl-transfer RNA from the acceptor to the donor site on the eukaryotic ribosome.
  • Toxin Fragment A inactivates EF-2 by catalyzing a reaction that yields free nicotinamide plus an inactive adenosine diphosphate-ribose-EF-2 complex (ADP-ribosylation).
  • Because the turnover of EF-2 is very slow and approximately only one molecule per ribosome is present in a cell, it has been estimated that one exotoxin molecule can inactivate the entire EF-2 content in a cell, completely terminating host cell protein synthesis.
  • It is assumed that the abrupt arrest of protein synthesis is responsible for the necrotizing and neurotoxic effects of diphtheria toxin.
  • Toxin synthesis  by lysogenized C diptheriae is regulated by a chromosomally encoded element, diphtheria toxin repressor (DTxR) which is  activated in the presence of high iron concentrations, and can bind to the toxin gene operator and prevent toxin production.
  • Low iron concentration and other factors such as osmolarity, amino acid concentrations and pH, however enhance the production of toxin.

Clinical manifestations of Corynebacterium diphtheriae

Respiratory diphtheria

  • Diphtheria toxin is absorbed into the mucous membranes and causes destruction of epithelium and a superficial inflammatory response.
  • The symptoms of diphtheria involving the respiratory tract develop after 2 to 4 days incubation period.
  • Organisms multiply locally on epithelial cells in the pharynx or adjacent surfaces and initially cause localized damage as a result of exotoxin activity.
  • The onset is sudden, with malaise, sore throat, exudative pharyngitis, and a low-grade fever.
  • The exudate evolves into a thick pseudomembrane composed of bacteria, lymphocytes, plasma cells, fibrin, and dead cells that can cover the tonsils, uvula, and palate and can extend up into the nasopharynx or down into the larynx
  • The regional lymph nodes in the neck enlarge, and there may be marked edema of the entire neck, with distortion of the airway, often referred to as “bull neck” clinically.
  • In critically ill patients, cardiac (necrosis of heart muscles) and neurologic complications (demylenation) is most significant.
  • Neurotoxicity is proportional to the severity of the primary disease, which is influenced by the patient’s immunity.
  • The majority of patients with severe primary disease develop neuropathy, initially localized to the soft palate and pharynx, later involving oculomotor and ciliary paralysis, with progression to peripheral neuritis.

Cutaneous diphtheria

  • Cutaneous diphtheria is acquired through skin contact with other infected persons.
  • The organism colonizes the skin and gains entry into the subcutaneous tissue through breaks in the skin.
  • A papule develops first and then evolves into a chronic, non-healing ulcer, sometimes covered with a grayish membrane
  • Systemic signs can develop.

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