Diphtheria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
Susceptible persons may acquire toxigenic diphtheria bacilli in the nasopharynx. The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and membrane formation. The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. The toxin is responsible for the major complications of myocarditis and neuritis and can also cause low platelet counts (thrombocytopenia) and protein in the urine (proteinuria). Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.[1][2]
Diphtheria toxin is a single, 60,000 molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalyzing the release of fragment A into the cell's cytoplasm.
Fragment A inhibits the synthesis of new proteins in the affected cell. It does this by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.
ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction's end-products, and high amounts will drive the reaction in the opposite direction.[citation needed]
Clinical disease associated with non-toxin-producing strains is generally milder. While rare severe cases have been reported, these may actually have been caused by toxigenic strains that were not detected because of inadequate culture sampling.Diphtheria toxin catalyzes the ADP-ribosylation of, and inactivates, the elongation factor eEF-2. In this way, it acts to inhibit translation during eukaryotic protein synthesis.
References
- ↑ Victor J Freeman (1951). "STUDIES ON THE VIRULENCE OF BACTERIOPHAGE-INFECTED STRAINS OF CORYNEBACTERIUM DIPHTHERIAE". Journal of Bacteriology. 61 (6): 675–688. PMC 386063. PMID 14850426.
- ↑ Freeman VJ, Morse IU (1953). "FURTHER OBSERVATIONS ON THE CHANGE TO VIRULENCE OF BACTERIOPHAGE-INFECTED AVIRULENT STRAINS OF CORYNEBACTERIUM DIPHTHERIAE". Journal of Bacteriology. 63 (3): 407–414. PMC 169283. PMID 14927573.