Diphtheria toxin

Diphtheria toxin is a potent cytotoxin produced by certain strains of the bacterium Corynebacterium diphtheriae, the pathogenic organism responsible for diphtheria. Diphtheria toxin is the primary virulence factor of the diphtheria bacterium, causing the symptoms associated with the disease by inhibiting protein synthesis in the host cells. Understanding the structure, mechanism of action, and effects of diphtheria toxin is crucial for the development of treatments and preventive measures against diphtheria.

Structure and Genetics

The gene that encodes diphtheria toxin, tox, is located on the bacteriophage β, which is a virus that infects some strains of Corynebacterium diphtheriae. The toxin itself is a single polypeptide chain composed of two subunits: the A subunit (active) and the B subunit (binding). The B subunit binds to the heparin-binding epidermal growth factor precursor on the surface of susceptible cells, facilitating the entry of the A subunit into the cell. Once inside, the A subunit enzymatically inactivates elongation factor-2 (EF-2), an essential protein for protein synthesis, leading to cell death.

Mechanism of Action

The mechanism of action of diphtheria toxin involves several steps. Initially, the toxin binds to the cell surface receptor through its B subunit. The toxin-receptor complex is then internalized by the cell through endocytosis. Inside the cell, the toxin undergoes a conformational change in the acidic environment of the endosome, which allows the A subunit to translocate into the cytosol. The A subunit, an ADP-ribosyltransferase, catalyzes the transfer of an ADP-ribose molecule from NAD+ to a specific histidine residue on EF-2, inactivating it. This inactivation halts protein synthesis, ultimately leading to cell death.

Clinical Manifestations

Diphtheria is characterized by the formation of a thick, gray pseudomembrane on the tonsils, pharynx, or nasal cavity, which can lead to difficulty breathing and swallowing. Toxin production can also cause myocarditis, polyneuritis, and other systemic effects due to the dissemination of the toxin through the bloodstream. The severity of the disease is directly related to the amount of toxin produced by the infecting strain of Corynebacterium diphtheriae.

Prevention and Treatment

The primary method of preventing diphtheria is through vaccination with the diphtheria toxoid, which is a modified form of the toxin that is non-toxic but still immunogenic. The DPT vaccine (diphtheria, pertussis, and tetanus) is commonly used worldwide to immunize children against these diseases. Treatment of diphtheria involves the administration of diphtheria antitoxin to neutralize the circulating toxin, as well as antibiotics to eradicate the bacterial infection.

Epidemiology

Diphtheria is more common in areas with poor sanitation and low vaccination rates. Before the introduction of vaccination, diphtheria was a major cause of illness and death in children. Thanks to widespread vaccination programs, the incidence of diphtheria has significantly decreased worldwide, although outbreaks still occur, particularly in areas where vaccination coverage is incomplete.

Conclusion

Diphtheria toxin plays a central role in the pathogenesis of diphtheria. Its ability to inhibit protein synthesis within host cells makes it a particularly dangerous virulence factor. Through the use of vaccines and prompt treatment, the impact of diphtheria toxin can be mitigated, preventing the severe outcomes associated with the disease.

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  Structure of the diphtheria toxin

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  Chemical structure of diphthamide