Diphtheria Toxin

Diphtheria is a local infection of the upper respiratory tract or skin that is caused by C. diphtheriae and spread from person to person by respiratory droplets or intimate contact. The characteristic lesion in the respiratory tract is a pseudomembrane that can sometimes cause obstruction of the airway. Diphtheria toxin produced at the site of local infection is distributed systemically and can cause myocarditis, polyneuritis and other complications. Respiratory diphtheria is usually caused by toxinogenic strains of C. diphtheriae, but cutaneous diphtheria is often caused by nontoxinogenic strains. The primary treatment for diphtheria is parenteral administration of diphtheria antitoxin to neutralize toxin that has not yet entered target cells. Antibiotics are used to eradi cate C. diphtheriae, eliminate the convalescent carrier state, and prevent spread of infection to susceptible contacts. Active immunization with diphtheria toxoid is highly effective in preventing diphtheria. Diphtheria is now rare in the United States and most developed countries, but it re-emerged as an epidemic disease in the early 1990s in the New Independent States of the former Soviet Union as a consequence of inadequate implementation of immunization programs during a period of severe socioeconomic disruption.

Toxinogenic conversion in C. diphtheriae was discovered in 1951, and in 1971 the structural gene for diphtheria toxin was shown to be phage-encoded. C. ulcerans and C. pseudotuberculosis, animal pathogens that occasionally cause disease in humans, can also carry tox+ corynephages and produce diphtheria toxin. Phage /?, the best characterized of the tox+ corynephages, is an inducible, temperate phage with a polyhedral head and a long noncontractile tail. It has a linear, double-stranded, 34.7 kbp DNA genome with cohesive ends. On the vegetative map the genes for head and tail components are located at opposite ends, and the tox gene is located centrally between the immunity region imm and the host range marker h. The phage integrates into the host chromosome by means of site-specific recombination between the phage locus attP and an homologous bacterial locus attB. The prophage map is a circular permutation of the vegetative phage map, and the tox gene in the prophage is adjacent to the attachment site. This location suggests that an ancestral tox gene located on the bacterial chromosome may have been acquired by the phage by illegitimate recombination during prophage excision. Several tox+ corynephages that vary with respect to virion morphology, antigenicity, and immunity specificity have homologous genomes, indicating that they constitute a family of related corynephages.

Diphtheria toxin (DT) is produced by C. diphtheriae as a secreted, extracellular protein of 535 amino acid residues. DT is cleaved by a protease such as trypsin or furin into an amino-terminal fragment A (21 kDa) and a carboxyl-terminal fragment B (37 kDa) that remain linked by a disulfide bond. The receptor-binding (R) domain of fragment B interacts with a receptor (heparin-binding EGF-like growth factor precursor) on susceptible cells and mediates entry of DT by endocytosis. Following acidification of the endosomes, the transmembrane (T) domain of fragment B inserts into the endosomal membrane and mediates translocation of fragment A into the cytoplasm. Fragment A catalyzes ADP-ribosylation of the unique diphthamide residue of EF-2, causing inactivation of EF-2, inhibition of protein synthesis and cell death. One molecule of fragment A in the cytoplasm can kill a susceptible eukaryotic cell. Exotoxin A from Pseudomonas aeruginosa ADP-ribosylates EF-2 in the same manner as DT, but it interacts with a different cell surface receptor and therefore differs from DT in its species and tissue specificity.

Production of diphtheria toxin by C. diphtheriae is regulated by iron, and maximal toxin production occurs during late log or stationary phase in iron-depleted medium. Transcription of the tox gene is repressed under high-iron growth conditions by the diphtheria toxin repressor (DtxR), an Fe2+-activated global regulatory protein that also controls production of corynebacterial siderophore, utilization of ferric siderophore complexes, and probably other functions in C. diphtheriae. DtxR binds to promoter/ operators that have a 19 bp core homologous to the palindromic consensus sequence TTAGGTTAGCC-TAACCTAA. The function of DtxR in C. diphtheriae is similar to that of the ferric uptake regulator (Fur) protein in E. coli, but DtxR and Fur bind to different consensus sequences and are therefore specific for different operators.

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