Diphtheria is a serious illness caused by the bacterium Corynebacterium diphtheriae. The bacterium itself is not the primary cause of the severe, often fatal, symptoms associated with the disease. Instead, the pathology arises from a powerful exotoxin the bacteria produce, known as the diphtheria toxin (DT). Understanding the precise mechanism by which this toxin operates reveals how it can so effectively shut down human cells and cause widespread damage throughout the body.
Toxin Structure and Cellular Entry
The diphtheria toxin is a single polypeptide chain. It consists of two main parts, designated the A subunit and the B subunit, which are connected by a disulfide bond. Each subunit has a distinct role. The B subunit is responsible for binding the toxin to the surface of a human cell, while the A subunit contains the enzymatic activity that ultimately damages the cell. At this early stage, the A subunit remains dormant, awaiting entry into the cell’s interior.
The process of entry begins when the B subunit recognizes and attaches to a specific protein on the surface of human cells. This target is the heparin-binding EGF-like growth factor (HB-EGF) precursor. This binding event tricks the cell into believing the toxin is a harmless substance that should be brought inside. The cell then initiates a process called receptor-mediated endocytosis.
During endocytosis, the cell membrane folds inward, engulfing the toxin-receptor complex and enclosing it within a small, membrane-bound bubble called an endosome. This vesicle transports the captured toxin into the cell’s cytoplasm. The toxin is now inside the cell, but it is still trapped within the endosome and its destructive A subunit is not yet active.
Activation and Translocation into the Cytoplasm
Once the endosome containing the diphtheria toxin is inside the cell, the cell actively pumps protons into the endosome, causing its internal environment to become increasingly acidic. This drop in pH is the trigger the toxin needs. The acidic conditions cause the B subunit to undergo a significant change in its three-dimensional shape.
This conformational change exposes a hidden region of the B subunit, which then inserts itself directly into the membrane of the endosome. This forms a small channel or pore, creating a direct passage to the cell’s cytoplasm. This pore is just large enough for the A subunit to pass through.
Simultaneously, the acidic environment and cellular enzymes break the disulfide bond that links the A and B subunits. Freed from the B subunit, the now-active A subunit is threaded through the pore created in the endosomal membrane. This translocation event moves the A subunit into the cytoplasm, where its targets are located. The B subunit remains behind, its job of delivering the toxic payload now complete.
Inhibition of Protein Synthesis
Now free in the cytoplasm, the A subunit functions as an enzyme. It catalyzes a specific chemical reaction known as ADP-ribosylation. This reaction targets a single molecule within the cell: eukaryotic Elongation Factor 2 (eEF-2). This protein is a component of the cell’s protein-making machinery.
The normal function of eEF-2 is to facilitate a process called translocation during protein synthesis. As the ribosome reads genetic instructions from an mRNA molecule to build a new protein, eEF-2 helps the ribosome move along the mRNA strand. This movement is necessary to read the next genetic codon and add the corresponding amino acid to the growing protein chain. Without eEF-2, this entire process grinds to a halt.
The toxin’s A subunit attacks eEF-2 by transferring an ADP-ribose group from a cellular molecule called NAD+ directly onto the eEF-2 protein. This modification permanently inactivates eEF-2. Because the A subunit is an enzyme, a single toxin molecule can carry out this reaction on many eEF-2 molecules. This catalytic nature means that even a minuscule amount of toxin can shut down all protein synthesis within the cell, leading to its death.
Cellular and Clinical Consequences
The shutdown of protein synthesis has severe consequences for the affected cell. Cells constantly need to produce new proteins to carry out functions, repair damage, and maintain their structure. Without this ability, the cell succumbs to necrosis, a form of cell death that results in the release of cellular contents and triggers a strong inflammatory response.
In a diphtheria infection, this process begins locally in the throat and upper airways where the bacteria reside. The widespread death of epithelial cells in this area leads to severe inflammation. This combination of dead cells, fibrin, and immune cells forms a thick, gray, adherent layer known as a pseudomembrane. This membrane can grow to obstruct the airway, potentially leading to suffocation.
If the diphtheria toxin gains access to the bloodstream, it can circulate throughout the body and cause systemic damage. The toxin will kill any susceptible cell it encounters that bears the HB-EGF receptor. Organs with high rates of protein turnover are particularly vulnerable. The heart is a common target, and toxin-induced damage can lead to myocarditis, abnormal heart rhythms, and heart failure. The toxin can also damage nerves, leading to paralysis, and the kidneys, causing acute kidney failure.