What is the pathophysiology of diphtherial Corynebacterium infections?

Updated: Jun 14, 2019
  • Author: Lynda A Frassetto, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Answer

C diphtheriae infection is typically characterized by a local inflammation, usually in the upper respiratory tract, associated with toxin-mediated cardiac and neural disease. Three strains of C diphtheriae are recognized, in decreasing order of virulence: gravis, intermedius, and mitis. These strains all produce an identical toxin, but the gravis strain is potentially more virulent because it grows faster and depletes the local iron supply, allowing for earlier and greater toxin production. Toxin production is encoded on the tox gene, which, in turn, is carried on a lysogenic beta phage. When DNA of the phage integrates into the host bacteria's genetic material, the bacteria develop the capacity to produce this polypeptide toxin.

The tox gene is regulated by a corynebacterial iron-binding repressor (DtxR). In the presence of ferrous iron, the DtxR-iron complex attaches to the tox gene operon, inhibiting transcription. In an iron-poor environment, the DtxR molecule is released and the tox gene is transcribed (see the illustration below).

The corynebacterial tox gene is regulated by the c The corynebacterial tox gene is regulated by the corynebacterial iron-binding repressor, labeled DtxR. Binding of ferrous iron to the DtxR molecule forms a complex that binds to the tox gene operator and inhibits transcription. Depletion of iron from the system removes the repression and allows the toxin to be produced.

The toxin is a single polypeptide with an active (A) domain, a binding (B) domain, and a hydrophobic segment known as the T domain, which helps release the active part of the polypeptide into the cytoplasm. In the cytosol, the A domain catalyzes the transfer of an adenosine diphosphate-ribose molecule to one of the elongation factors (eg, elongation factor 2 [EF2]) responsible for protein synthesis. This transfer inactivates the factor, thereby inhibiting cellular protein synthesis. Inhibiting all the protein synthesis in the cell causes cell death.

In this manner, the toxin is responsible for many of the clinical manifestations of the disease. As little as 0.1 µg can cause death in guinea pigs. In 1890, von Behring and Kitasato demonstrated that sublethal doses of the toxin induced neutralizing antibodies against the toxin in horses. In turn, this antiserum passively protected the animals against death following challenge infection. By the early 1900s, treating the toxin with heat and formalin was discovered to render it nontoxic. When injected into recipients, the treated toxin induced neutralizing antibodies. By the 1930s, many Western countries began immunization programs using this toxoid.

Adhesion of pathogenic corynebacteria to host cells is a crucial step during infection. Adhesion to host cells is mediated by filaments called fimbrae or pili; the minor pilins SpaB and SpaC are specific adhesins that covalently bind the bacteria to the cell membranes of the respiratory epithelium. [11]

More recently, iron levels have been shown to regulate the adhesion properties of the bacteria; iron-limited conditions promote changes in the cell-surface residues, leading to increased hemagglutination activity and decreased binding to glass. [12]


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