Pathogenesis of diphtheria

Mechanism of exotoxin action

The main virulence factor of the pathogen is the diphtheria exotoxin, consisting of high-molecular-weight dermonecrotizin and low-molecular-weight histotoxin.

As long as the corynebacterium is in a high-iron environment, it produces dermonecrotizin. As soon as iron stores are depleted, active synthesis of histotoxin begins. This native toxin has two subunits:

• Fragment B acts as a receptor guide, binding to the membrane of the eukaryotic target cell.
• Fragment A penetrates into the cytoplasm, where it exhibits enzymatic activity. It inactivates the transferase responsible for the elongation of the polypeptide chain on ribosomes.

As a result, intracellular protein synthesis is completely blocked, leading to the death (necrosis) of the affected cell.

Local changes and membrane formation

Having overcome the protective barriers of the nasopharyngeal or oropharyngeal mucous membranes, the pathogen attaches to the epithelium and begins to multiply. Released enzymes and toxins damage epithelial cells and the endothelium of the microvasculature. This causes exudation of plasma rich in fibrinogen.

Upon contact with tissue thromboplastin from destroyed cells, fibrinogen is converted into insoluble fibrin.

• On stratified squamous epithelium (e.g., in the oropharynx), deep diphtheritic inflammation develops. The dense fibrinous membrane plays a dual role: it prevents bacteria from breaking into the bloodstream (bacteremia does not develop), but it creates ideal conditions underneath for further toxin production.
• On simple columnar epithelium (larynx, trachea, bronchi), superficial croupous inflammation occurs. The membranes are easily detached, so toxemia is mild, but there is a risk of airway obstruction (croup).

Systemic toxemia and target organs

The absorption of cell destruction products and histotoxin into the systemic circulation triggers a general toxic syndrome. The toxin increases vascular permeability, impairs blood rheology, and causes microcirculatory disorders leading to tissue hypoxia.

The cytotoxic effect of histotoxin is strictly targeted at specific target cells:

1. Heart (myocardium): destruction of mitochondria, blockade of carnitine, and release of lysosomal enzymes cause fatty transformation of the myocardium. This reduces contractility and impairs conductivity.
2. Nervous system: destruction of the myelin sheaths of peripheral and cranial nerves occurs, clinically manifesting as flaccid paresis and paralysis.
3. Adrenal glands: synthesis of glucocorticoids and catecholamines drops, threatening acute adrenal insufficiency and shock.
4. Kidneys: tubular epithelial necrosis leads to the development of necrotic nephrosis and acute renal failure (ARF).

Early and late complications

The nature of complications in diphtheria depends on the period of the disease:

• Early specific complications develop during the peak period (anginal period). They are caused by direct toxic damage to target organs (myocarditis, neuritis, nephrosis).
• Late specific complications manifest in the convalescence stage. They are predominantly immunopathological in nature. They are based on the formation of immune complexes (including due to the administration of equine antitoxic serum) and the initiation of autoimmune reactions against the tissues of the myocardium and nerve trunks.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Molecular structure of histotoxin (functions of subunits A and B).
• Pathophysiology of infectious-toxic shock development in toxic diphtheria.
• Features of diphtheritic and croupous inflammation on different types of epithelium.
• Impact of immunization with anatoxins (DT, DTaP) on the pathogenesis of infection.
• Epidemiological role of bacterial carriers and the impact of ARVI on pathogen shedding.

Other topics in the "Respiratory Infections" section

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