Pathogenic Clostridia, including Botulism and Tetanus (page 3)
(This chapter has 4 pages)
© Kenneth Todar, PhD
Clostridium tetani is the causative agent of tetanus.
The organism is found in soil, especially heavily-manured soils, and in
the intestinal tracts and feces of various animals. Carrier rates in
vary from 0 to 25%, and the organism is thought to be a transient
of the flora whose presence depends upon ingestion. The organism
terminal spores within a swollen sporangium giving it a distinctive
appearance. Although the bacterium has a typical Gram-positive cell
it may stain Gram-negative or Gram-variable, especially in older cells.
Clostridium tetani Gram stain.
terminal endospores in a swollen sporangium exhibiting "tennis racket" shape. CDC
Tetanus is a highly fatal disease of humans. Mortality rates
vary from 40% to 78%. The disease stems not from invasive infection but
from a potent neurotoxin (tetanus toxin or tetanospasmin)
produced when spores germinate and vegetative cells grow after gaining
access to wounds. The organism multiplies locally and symptoms appear
from the infection site.
Because of the widespread use of the tetanus toxoid for
immunization, fewer than 150 cases occur annually in the U.S., but the
disease is a significant problem world-wide where there are >300,000
cases annually. Most cases in the U.S occur in individuals over
age 60, which is taken to mean that waning immunity is a significant
Pathogenesis of tetanus
Most cases of tetanus result from small puncture wounds or lacerations
which become contaminated with C. tetani spores that germinate
produce toxin. The infection remains localized, often with only minimal
inflammatory damage. The toxin is produced during cell growth,
and lysis. It migrates along neural paths from a local wound to sites
action in the central nervous system. The clinical pattern of
tetanus consists of severe painful spasms and rigidity of the
muscles. The characteristic symptom of "lockjaw" involves spasms of
the masseter muscle. It is an early symptom which is followed by
rigidity and violent spasms of the trunk and limb muscles. Spasms of
pharyngeal muscles cause difficulty in swallowing. Death usually
from interference with the mechanics of respiration.
Sir Charles Bell's portrait
of a soldier dying of tetanus. The characteristic rigidity of the body
is referred to as opisthotonos and risus sardonicus. Original in the
College of Surgeons of Edinburgh, Scotland.
Neonatal tetanus accounts for about half of the tetanus
in developing countries. In a study of neonatal mortality in
112 of 330 infant deaths were due to tetanus. Neonatal tetanus follows
infection of the umbilical stump in infants born to nonimmune mothers
the infant has not acquired passive immunity). It usually results from
a failure of aseptic technique during birthing procedures, but certain
practices may contribute to infection.
There have been 11 strains of C. tetani distinguished primarily
on the basis of flagellar antigens. They differ in their ability to
tetanus toxin (tetanospasmin), but all strains produce a toxin which is
identical in its immunological and pharmacological properties.
is encoded on a plasmid which is present in all toxigenic
Tetanus toxin is one of the three most poisonous substances known to
other two being the toxins of botulism and diphtheria. The toxin is
by growing cells and released only on cell lysis. Cells lyse naturally
during germination the outgrowth of spores, as well as during
growth. After inoculation of a wound with C. tetani spores, only a
amount of spore germination and vegetative cell growth are required
the toxin is produced.
The bacterium synthesizes the tetanus toxin as a single 150kDa
chain (called the progenitor toxin), that is cleaved extracellularly by
a bacterial protease into a 100 kDa heavy chain (fragment B) and a
light chain (fragment A), which remain connected by a disulfide bridge.
The specific protease that cleaves the progenitor toxin can be found in
culture filtrates of C. tetani. Cleavage of the progenitor
into A and B fragments can also be induced artificially with trypsin.
Tetanus toxin is produced in vitro in amounts up to 5 to 10% of the
bacterial weight. Because the toxin has a specific affinity for nervous
tissue, it is referred to as a neurotoxin. The toxin has no
useful function to C. tetani. Why the toxin has a specific
on nervous tissue, to which the organism naturally has no access, may
an anomaly of nature. The toxin is heat labile, being destroyed at 56oC
in 5 minutes, and is O2 labile. The purified toxin rapidly
toxoid at 0oC in the presence of formalin.
Tetanospasmin initially binds to peripheral nerve terminals. It
is transported within the axon and across synaptic junctions until it
the central nervous system. There it becomes rapidly fixed to
at the presynaptic inhibitory motor nerve endings, and is taken up
into the axon by endocytosis. The effect of the toxin is to block
release of inhibitory neurotransmitters (glycine and gamma-amino
acid) across the synaptic cleft, which is required to inhibit nervous
impulse. If nervous impulses cannot be checked by normal inhibitory
it produces the generalized muscular spasms characteristic of tetanus.
Tetanospasmin appears to act by selective cleavage of a protein
of synaptic vesicles, synaptobrevin II, and this prevents the
of neurotransmitters by the cells.
The receptor to which tetanospasmin binds has been reported as
GT and/or GD1b, but its exact identity is still in question. Binding
to depend on the number and position of sialic acid residues on the
Isolated B fragments, but not A fragments, will bind to the
The A fragment has toxic (enzymatic) activity after the B fragment
its entry. Binding appears to be an irreversible event so that recovery
on sprouting a new axon terminal.
Unlike other toxigenic diseases, such as diphtheria, recovery from the
usually does not confer immunity, since even a lethal dose of
is insufficient to provoke an immune response.
Prophylactic immunization is accomplished with tetanus toxoid, as
of the DPT (DTaP) vaccine or the DT (TD) vaccine. Three injections are
in the first year of life, and a booster is given about a year later,
again on the entrance into elementary school.
Whenever a previously-immunized individual sustains a potentially
wound, a booster of toxoid should be injected. Wherever employed,
programs of immunization with toxoid have led to a striking reduction
the incidence of the disease.