The diphtheria toxin is a powerful bacterial byproduct that causes the severe symptoms of diphtheria disease. Recognized as a major health threat for centuries, with reports of a deadly “strangulation” disease appearing as early as the 1600s, its identification in the late 19th century marked a turning point. Until the mid-1920s, diphtheria was a leading cause of childhood mortality.
The Toxin’s Origin and Composition
The diphtheria toxin originates from the bacterium Corynebacterium diphtheriae, but only when infected by a bacteriophage carrying the tox gene. Thus, not all Corynebacterium diphtheriae strains produce the toxin. The toxin is a single polypeptide chain of 535 amino acids, which can be proteolytically cleaved into two main fragments: an N-terminal fragment A and a C-terminal fragment B.
This protein possesses three distinct functional domains: a catalytic domain (C), a transmembrane or translocation domain (T), and a receptor-binding domain (R). Fragment A contains the catalytic domain, while fragment B comprises both the receptor-binding and transmembrane domains. These domains are interconnected, allowing for a coordinated sequence of events that leads to cellular damage.
How the Toxin Attacks Cells
The diphtheria toxin’s action begins with its receptor-binding domain (R domain) attaching to specific receptors on human cells, particularly the heparin-binding epidermal growth factor-like growth factor (HB-EGF) receptor. This binding initiates receptor-mediated endocytosis, where the toxin-receptor complex is internalized into the cell within endosomal vesicles.
Once inside the endosome, the acidic environment triggers a conformational change in the toxin’s transmembrane domain (T domain). This allows the T domain to insert into the endosomal membrane, creating a pore. Through this channel, the catalytic domain (C domain) is translocated into the cell’s cytoplasm.
Upon reaching the cytosol, the catalytic domain becomes enzymatically active. It performs ADP-ribosylation on a modified histidine residue (diphthamide) on eukaryotic elongation factor 2 (EF-2). This modification inactivates EF-2, which is a protein essential for protein synthesis. The inhibition of protein synthesis ultimately leads to cell death. A single molecule of the catalytic domain entering the cytosol is sufficient to kill a cell, demonstrating the toxin’s extreme potency.
Impact on the Body and Diphtheria Disease
Once the diphtheria toxin enters the bloodstream, it can spread throughout the body, causing systemic effects beyond the initial infection site in the throat or skin. While the toxin does not target a single cell type, its effects are most commonly observed in the heart muscle, nervous system, and kidneys. Damage to these organs results from the toxin’s ability to inhibit protein synthesis in various cell types.
In the heart, the toxin can cause myocarditis, an inflammation of the heart muscle. This can lead to cardiac complications such as arrhythmias, including first, second, or third-degree heart block, and potentially circulatory collapse. Myocarditis can manifest one to two weeks after initial diphtheria symptoms, sometimes worsening as throat symptoms improve.
The nervous system can also be affected, leading to neuropathy, which may present as paralysis. This nerve damage can affect areas like the pharynx, larynx, palate, and even vision. Kidney injury has also been documented as an effect of the circulating exotoxin.
Counteracting the Toxin’s Effects
The primary method for neutralizing the diphtheria toxin is through the administration of diphtheria antitoxin (DAT). This antitoxin is derived from equine (horse) blood and contains antibodies that specifically bind to and inactivate circulating toxin molecules. By binding to the toxin, DAT prevents it from attaching to and entering human cells, stopping the progression of cellular damage. Early administration of DAT is important, as it is most effective before the toxin has irreversibly bound to and entered cells.
For long-term protection against diphtheria, vaccination plays a significant role. The diphtheria vaccine utilizes a modified version of the toxin, known as a toxoid. A toxoid is created by treating the diphtheria toxin with substances like formalin, which reduces its toxicity while retaining its ability to stimulate an immune response.
When this toxoid is introduced into the body, the immune system recognizes it as a foreign substance and produces its own antibodies. These antibodies provide long-lasting immunity, ready to neutralize the diphtheria toxin if a vaccinated individual is exposed to it in the future. The diphtheria toxoid is commonly administered as part of combination vaccines like DTaP, which also protect against tetanus and pertussis.