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Chapter: Microbiology and Immunology: Bacteriology: Clostridium

Pathogenesis and Immunity - Clostridium tetani

C. tetani is a noninvasive bacillus. It causes disease only by pro-duction of toxins, which are most important virulence factors.

Pathogenesis and Immunity

C. tetani is a noninvasive bacillus. It causes disease only by pro-duction of toxins, which are most important virulence factors (Table 29-3).

 Virulence factors

C. tetani produces the following toxins: (a) tetanolysin,(b) tetanospasmin, and (c) neurotoxin or nonspasmogenic toxin. Tetanolysin and tetanospasmin are two major toxins, which are pharmacologically and antigenically distinct. Nonspasmogenic toxin or neurotoxin is identified recently.

Tetanospasmin: Tetanospasmin is the toxin responsible forthe clinical manifestations of tetanus. The toxin is produced during the stationary phase of growth but is released only after the lysis of bacteria.

·           Tetanospasmin is a protein and is synthesized as a single polypeptide chain of molecular weight (MW) 151,000 Da. On release from the bacillus, the peptide is split by an endog-enous protease into two chains: a light chain (A) of 52,000 MW protein and a heavy chain (B) of 93,000 MW protein; the two chains are joined by noncovalent forces of a disulfide bond.

·           The purified toxin is extremely potent. The minimum lethal dose (MLD) of toxin for animals is 50–75 10–6 mg and for humans is 130 ng.

·           Different species of animals show a wide variety in their sus-ceptibility to tetanospasmin. Birds and reptiles are highly resistant to the toxin. Horses are most susceptible to the toxin followed by guinea pigs, goats, and rabbits in the descending order.

·           The toxin acts by preventing the release of neurotransmit-ters, such as gamma-aminobutyric acid (GABA), glycine, etc., thereby specifically blocking synaptic inhibition in the spinal cord. This leads to unregulated spread of impulses, inhibited anywhere in the central nervous system (CNS).

·           The binding of toxin is irreversible.

·           Tetanus toxoid is antigenic but nontoxic. Tetanus toxin is made into toxoid by treating it with formaldehyde.

Tetanolysin: Tetanolysin is an oxygen- and heat-labile hemo-lysin. It is antigenically related to other clostridial hemolysins and streptolysin O. The toxin is of doubtful pathogenicity and appears not to play any role in the pathogenesis of tetanus.

Neurotoxin: This is a third toxin recently identified. It is anonspasmogenic and peripherally active neurotoxin. The role of this toxin in pathogenesis of tetanus is not understood.

 Pathogenesis of tetanus

Tetanus is caused by entry of the C. tetani spores. Under anaer-obic conditions, the spores germinate to vegetative form and subsequently produce toxins, such as tetanospasmin and tetanolysin, under favorable conditions of anaerobiosis. The conditions that favor anaerobiosis in tissues include wounds with low oxidation–reduction potential, such as those with (a) dead devitalized tissue, (b) a foreign body, or (c) active infec-tion. Tetanospasmin is absorbed locally and at the nervous system peripherally at the myoneural junction and is trans-ferred centripetally into neurons of the CNS.

·           The heavy chain (100 kDa) of the toxin is responsible for specific binding to neural cells and for protein transport.

·           The light chain blocks the release of two major inhibitory neurotransmitters, such as GABA and glycine. This leads to failure of inhibition of motor reflex responses to sensory stimulation. This results in generalized contraction of the agonist and antagonist musculature—the characteristics of a tetanic spasm in the absence of reciprocal inhibition.

      The shortest peripheral nerves transmit toxin quickly to the CNS, which leads to early symptoms of facial distortion and back and neck stiffness.

The toxicity of tetanospasmin depends upon the route of administration of the toxin. The route of administration also modifies the course of clinical manifestation of the disease.

·           Intraneural injection and injection directly into the CNS is most lethal.

·           Intravenous, intramuscular, and subcutaneous injections are effective but toxin given orally is ineffective because toxin is destroyed by enzymes present in the gastrointestinal tract.

Tetanus in experimental animals: The experimental teta-nus in animals, such as mice, is also dependent on the route of administration of toxins.

Intramuscular injection of toxin:This causes ascendingtetanus. Intramuscular injection in one of the hind limbs is associated with appearance of tonic spasm of the muscles in the injected limb first. This is due to toxin acting on the seg-ment of spinal cord.

The toxins act by preventing the inhibition or removing the nerve impulse, once they cross the synaptic junctions. The nerve continues to send impulses resulting in spasmodic contractions or tetani of the affected muscles.

Muscle stiffness is the early symptom, with jaw muscles often developing symptoms first. This condition is called lockjaw; with progression of disease, spasm develops in other mus-cles. The spasm, although brief, occurs frequently and causes immense pain and exhaustion. This condition is called local tetanus. Subsequent spread of the toxin up the spinal cord causes ascending tetanus. In this condition, the opposite hind limb, trunk, and fore limbs are involved.

Intravenous injection of toxin:This causes descending tetanus.In this condition, spasticity develops first in the muscles of the head and neck and then spreads downward, which resembles naturally occurring tetanus in humans.

 Host immunity

Specific antibodies produced against tetanus toxin are pro-tective. Antibodies specifically combine with free toxin and prevent the action of the toxin.

·           Prevalence of protective immunity to tetanus is greater in children and in persons aged between 6 and 39 years.

·            Protective immunity from tetanus decreases in older people. Serological study for immunity has shown a low level among elderly individuals in many countries. Approximately 50% of persons older than 50 years are nonimmune, because they never were vaccinated or did not receive appropriate booster doses.

·           Clinical tetanus does not produce a state of immunity; hence, patients who survive the disease require active immunization with tetanus toxoid to prevent a recurrence of the disease.

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