Diphtheria Exotoxin

The exotoxin-producing diphtheria bacteria carries a bacteriophage (bacterial virus) gene (Dtox) that codes for the exotoxin. Expression of the Dtox gene is controlled by a diphtheria iron-dependent repressor gene (DtoxR). If sufficient iron is available, the DtoxR gene synthesizes a repressor protein that inhibits the transcription and translation of the Dtox gene. When iron stores are exhausted, the repressor protein is not synthesized and the toxin gene is transcribed and translated.

Diphtheria Pathophysiology

Diphtheria organisms colonize the tonsils and the pharynx. The secreted exotoxin destroys surrounding tissue, and leakage of blood and plasma in the necrotic tissue activates fibrin, which creates a pseudomembrane at the back of the throat. If untreated, the membrane ultimately obstructs airflow and causes death.

The exotoxin is also transported to the heart, muscle, adrenal glands, kidneys, liver, and spleen. The most frequent diphtheria complications are myocarditis and neuritis. Abnormal heart rhythms occur early in the infection, and necrosis of heart muscle often leads to heart failure.

Treatment

Diphtheria Vaccine

Diphtheria toxoid is usually included with other antigens in combination vaccines of varying strengths. In the description of diphtheria vaccines, uppercase letters (D, P, or T) denote full strength diphtheria, pertussis, and tetanus. Lowercase letters (d and p) indicate reduced concentrations of diphtheria and pertussis in the vaccine. Acellular components of a vaccine are represented by the lowercase “a” (DTaP).

DTaP and DT vaccines are used through 6 years of age. The DTaP also is formulated with inactivated polio–hepatitis B (Pediarix). Adult Td can be used to vaccinate individuals 7 years and older. Tdap vaccines are available for children between 10 and 18 years of age (Boostrix), and Adacel is approved for individuals 11 to 64 years of age.

Following a four-vaccination series over 8 months, the clinical efficacy is 97%. However, diphtheria immunity wanes with age, and children and adults are at risk for contracting the disease. To maintain protective immunity, children vaccinated with DTaP should receive booster doses at 4 to 6 years of age and every 10 years thereafter. Older children vaccinated with adult Td or Tap should receive a booster shot every 10 years.

Pertussis Toxin

The B. pertussis toxin (PTx) is an A+B subunit toxin. Attachment to the cell is facilitated by the B units, and the A unit is responsible for the toxicity. PTx is a ribosyl transferase, which binds ADP-ribose to a membrane-bound regulatory G1 molecule. Inactivation of the G1 protein allows uncontrolled conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Accumulating cAMP disrupts normal cellular function and alters hormone activity. For example, increased cAMP levels increase sensitivity to histamine, which results in increased capillary permeability, hypotension, and shock. PTx also downregulates both cellular and antibody-mediated immune responses, increasing the risk for secondary infections.

Tracheal Cytotoxin

The tracheal cytotoxin is a cell wall peptidoglycan fragment and cannot be classified as an exotoxin or an endotoxin. The toxin kills ciliated epithelial cells in the respiratory tract and stimulates the release of interleukin 1 (IL-1), which acts as an endogenous pyrogen.

Dermonecrotic Lethal Toxin

Dermonecrotic lethal toxin is an exotoxin that causes local necrosis of tissue adjacent to areas colonized by pertussis. The role of the lethal toxin in the pathophysiology of whooping cough is unknown.

Treatment

Vaccine

The original whole-cell, inactivated pertussis (wBP) vaccine was developed in the 1930s. Although the vaccine was effective, it contained small amounts of the lipopolysaccharide endotoxin. The endotoxin caused significant adverse health effects, including acute encephalopathy, febrile seizures, and hypotonic or hypertonic episodes. The vaccine has been discontinued in the United States.

Tetanus Toxin

C. tetani spores infect humans by accident, through a deep puncture wound. A deep wound ensures an oxygen-depleted (anaerobic) environment, which allows spores to germinate into vegetative bacteria. Vegetative bacteria release two protein exotoxins—tetanolysin and tetanospasmin. Tetanolysin lyses red blood cells but has no other physiologic function. Tetanospasmin is responsible for the recognized pathophysiology of tetanus.

Tetanospasmin is a 150-kiloDalton (kDal) A+B toxin. The B subunit binds to membrane gangliosides on neural pathways, and the complete toxin is transported to peripheral nerve end plates, the sympathetic nervous system, the spinal cord, and the brain. In the nerve endings, the A subunit inactivates synaptobrevin and prevents the release of gamma amino butyric acid (GABA) and glycine, which normally control the release of acetylcholine. Uncontrolled acetylcholine synthesis and increased nerve firing cause unpredictable muscle contractions, spasms, and seizures characteristic of tetanus.

Clostridium tetani and Disease

Four clinical forms of tetanus have been described: (1) generalized (most common), (2) local (common), (3) cephalic (rare), and (4) neonatal (common in the developing countries).

Treatment

Tetanus Vaccine

Like the diphtheria toxin, tetanus toxin is treated with formalin to create a toxoid. It is offered as a fluid toxoid or absorbed to aluminum hydroxide. Although both formulations induce antibodies, a higher antibody response and duration of protection is induced by the adsorbed toxoid. Tetanus toxoid is available as a stand-alone vaccine or combined with diphtheria toxoid and acellular pertussis to form the DTaP vaccine. Three doses of tetanus toxoid in children 7 years of age and older or four doses in infants confer immunity in 100% of individuals. Without booster doses, immunity wanes, and antibody levels fall below the protective levels after 10 years.

Treatment

Vaccines

Pneumococcal Diseases

From the initial colonization in the respiratory tract, the organism spreads into the paranasal sinuses, the middle ear, the lung, and the brain. In children and older adults, pneumococci also cause osteomyelitis, endocarditis, cellulitis and brain abscesses.