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Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
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1. TOXINS OF CLOSTRIDIUM TETANI
Dr. N. Babu Prasath
P-2185
Division of Pathology
Indian Veterinary Research Institute
Izatnagar, Bareilly
2. INTRODUCTION
• Tetanus is a bacterial disease
caused by anaerobic bacteria -
Clostridium tetani
• Large size
• Gram negative
• Spore forming
• Strict anaerobic
• Non invasive
• Highly toxigenic
• Slightly proteolytic
• The organisms found in soil
and are common in the feces
of many species
3. INTRODUCTION
• Spores are spherical, terminal
and bulging (drum stick/Tennis
rocket)
• The spores are resistant to most
sporicidal agents and can
remain viable for years.
4. • Spore inoculation occurs via a
disrupted skin barrier, most
often after a penetrating injury
• Spore vegetate, proliferate and
produce the toxin.
• Deep wounds with poor
oxygenation are most
susceptible for vegetation.
• Liberates exotoxins under
anaerobic conditions.
INTRODUCTION
5. • Although all domestic animals are susceptible to tetanus
– Horses are most sensitive
– Dogs and ruminants are more resistant.
– Cats appear to be very resistant.
• Acute onset of hypertonia, painful muscular
contractions, generalized muscle spasms
INTRODUCTION
6. • Case 7 in the Edwin Smith Surgical Papyrus discusses a
patient with a penetrating skull wound who experiences
trismus and nuchal rigidity. These findings were well known
to the Egyptian physician who used them to help formulate
the prognosis.
• Hippocrates described the disorder clearly and observed
that these manifestations were “apt to supervene on the
wound of a membrane, or of muscles, or of punctured
nerves, when, for the most part, the patients die; for,
“spasm from a wound is fatal”
• Galen noted that cutting a nerve in tetanus stopped the
movement but paralyzed the innervated part.
• John of Arderne (1307 to 1380), often thought to be the first
English surgeon-author, described a case of tetanus in which
trismus (“taken with the cramp on his cheeks”) began 11
days after a gardening injury.
HISTORY
7. • In the eighteenth century, tetanus was thought to be a
consequence of nerve injury. However, the spasms of
generalized tetanus were frequently confused with the
convulsions of epilepsy.
• Sir Charles Bell, a noted illustrator and a surgeon, included a
patient with tetanus infection in his 1824 text
HISTORY
Sir Charles Bell portrait of Ophisthotonus of a soldier dying
of tetanus (1809)
8. • Gowers - a strychnine-like toxin isolated from anaerobic soil
bacteria.
• Six years later, Behring and Kitasato proved that immunization
with an inactivated derivative of this bacterial extract
prevented tetanus
• In 1829, Ceroli described the use of morphine as a treatment
for tetanus.
• Claude Bernard, - curare was employed with some rare
successes (and some dramatic failures) in France, Germany ,
the United States, and England.
• Meltzer and Auer employed magnesium salts to treat tetanus
patients at the dawn of the twentieth century.
HISTORY
9. • Two types of exotoxins
– Tetanolysin
(Nonspasmogenic)
– Tetanospasmin
(Spasmogenic)
TETANOTOXIN/TETANITOXIN
• Tetanus toxin spreads through tissue spaces into
the lymphatic and vascular systems.
• It enters the nervous system at the neuromuscular
junctions and migrates through nerve trunks and into
the CNS.
• Tetanospasmin is one of the three most potent toxin
known, other two are botulinum toxin and diptheria toxin
10. • Tetanolysin is an oxygen-sensitive hemolysin similar
to streptolysin and the θ-toxin of Clostridium
perfringens.
• It may play a part in establishing infection at the site
of inoculation
• Facilitates the spread of infection by increasing the
amount of local tissue necrosis.
TOXIN 1 - TETANOLYSIN
11. • Nonspasmogenic toxin
• Haemolysin toxin
• The molecular weight is of
50 KDa (50,000 to 55,000
daltons)
TOXIN 1 - TETANOLYSIN
12. • The mechanism of action
– Bind to membrane cholesterol and form pores in the
cytoplasmic membranes
– causing permeability changes in cell membarne and
other biologic membranes resulting in cell lysis
(cytolysis) so called as cytolysins
TOXIN 1 - TETANOLYSIN
13. • Affect a variety of
cells including
erythrocytes,
neutrophils,
macrophages,
fibroblasts and
platelets.
TOXIN 1 - TETANOLYSIN
14. • Tetanospasmin is one of the
most potent toxins known to
man based purely on weight.
• Spasmogenic toxin
• Potent neurotoxin
• Abbreviated as TeNT
• Molecular weight of 150 kDa
(150000 daltons)
• The estimated lethal dose
equals only 2.5 ng/kg body
weight
TOXIN 2 - TETANOSPASMIN
15. • It is transcribed from the tetX gene
• The tetX gene encoding this protein is located on the
pE88 plasmid
TOXIN 2 – TETANOSPASMIN
STRUCTURE
16. • Translated as one protein which is
subsequently cleaved into two parts
– a 100 kDa heavy chain (Hc) or B-chain
– a 50 kDa light (Lc) or A-chain.
• The chains are connected by a disulfide bond.
TOXIN 2 – TETANOSPASMIN
STRUCTURE
17. TOXIN 2 – TETANOSPASMIN
STRUCTURE
• B-chain have two domains
– Binding domain /Carboxyl terminal
/ β Trefoil domain
• 50 Kda
• Binds to
dissialogangliosides (GD2 and
GD1b) on the neuronal
membrane
– Translocation domain / Amino
terminal / Jelly roll domain
• 50 Kda
• Aids in the movement of the
protein across that membrane
and into the neuron.
x-ray crystal
structure of Hc at
2.7-Å resolution
18. • A-chain / Light chain (Lc)
– 50KDa
– Catalytic domain
– Contains a zinc endopeptidase, attacks the vesicle-
associated membrane protein (VAMP).
TOXIN 2 – TETANOSPASMIN
STRUCTURE
19.
20.
21. • The action of TeNT involves two major process
• 1. Transport
– Specific binding in the periphery neurons
– Retrograde axonal transport to the central nervous system
(CNS)
– Transcytosis from the axon into the inhibitory interneurons
• 2. Action
– Temperature and pH mediated translocation of the light
chain into the cytosol
– Reduction of the disulfide bridge to thiols, severing the link
between the light and heavy chain
– Cleavage of synaptobrevin by light chain
MECHANISUM OF ACTION
22. • A bacterial protease cleaves the disulfide bond between
the toxin's heavy (100 kDa) and light (50 kDa) chains.
• The heavy chain divided into fragments B and C by
pepsin, mediates binding of the toxin to presynaptic
receptors and allows for receptor-mediated endocytosis
MECHANISUM OF ACTION
23. • Transport begins with the B-
chain mediating the
neurospecific binding of TeNT
to the nerve terminal
membrane.
• It binds to
– GT1b polysialogangliosides
and
– GPI anchored
protein receptor
• Once it is bound the neurotoxin
is then endocytosed into the
nerve
MECHANISUM OF ACTION
STEP 1
24. • Axonal transport - begins to travel through the axon to
the spinal neurons.
• It is the retrograde axonal transport by using dyneins
MECHANISUM OF ACTION
STEP 2
25. • Transcytosis (cytopempsis) - transcellular transport in which
various macromolecules are transported across the interior of
a cell. Macromolecules are captured in vesicles on one side of
the cell, drawn across the cell and ejected on the other side
MECHANISUM OF ACTION
STEP 3
Example
26. • Once the vesicle is in the inhibitory interneuron its
translocation is mediated by pH and temperature
(specifically a low or acidic pH in the vesicle and standard
physiological temperatures)
MECHANISUM OF ACTION
STEP 4 (Translocation of Lc)
27. • Acidic pH translocate the Lc into the cytosol
• Once translocated into the cytosol, chemical reduction of the
disulfide bond to separate thiols occurs by the
enzyme NADPH-thioredoxin reductase-thioredoxin.
MECHANISUM OF ACTION
STEP 4 (Translocation of Lc)
28. • The L chain is a metalloprotease, which cleaves
synaptobrevin, a membrane protein (SNARE) in synaptic
vesicles necessary for the release of neurotransmitters
• The light chain is then free to cleave the Gln76-Phe77
bond of synaptobrevin
MECHANISUM OF ACTION
STEP 5 (Disulphide bond reduction)
29. • Synaptobrevin is an integral V-SNARE PROTEIN necessary for
vesicle fusion to membranes.
• Cleavage of synaptobrevin affects the stability of the SNARE core
by interfering with exocytosis of neurotransmitters from
inhibitory interneurons.
MECHANISUM OF ACTION
STEP 6 (Cleavage of Snaptobrevin)
Soluble NSF
attachment
protein receptor
N ethylmaleimide
sensitive factor
30.
31. • The blockage of the
inhibitory
neurotransmitters is the
direct cause of the
physiological effects that
TeNT induces.
– γ-aminobutyric
acid (GABA)
– glycine
MECHANISUM OF ACTION
Inhibition of inhibitory neurotransmittor
32. MECHANISUM OF ACTION
Inhibition of inhibitory neurotransmittor
• Glycine is the neurotransmitter for primary
inhibitory interneurons such as the
Renshaw cell
– Tetanospasmin prevents Ca2+
-
dependent release of glycine
• GABA is the inhibitory transmitter for
descending pathways.
– Blocking GABA inhibits the inhibitory
action on motor neurons
33. MECHANISUM OF ACTION
Inhibition of inhibitory neurotransmittor
• Results in unopposed excitation of
spinal neurons and muscle
contraction leads violent spastic
paralysis
• Tetanus toxin can also block
sympathetic preganglionic neurons
resulting in autonomic
dysfunction.
• Finally, tetanus toxin may bind
directly at neuromuscular junctions
and cause neuromuscular
facilitation.
34. • The combined consequence is dangerous overactivity in
the muscles from the smallest sensory stimulus as the
damping of motor reflexes is inhibited, leading to
generalized contractions of musculature termed a
"tetanic spasm”.
MECHANISUM OF ACTION
Continuous contraction of muscles
35. • The relatively short cranial nerves,
– The primary motor part of seventh (facial) and fifth
(trigeminal) nerve innervating the powerful facial and
masseter muscles respectively, mediate both risus
sardonicus (a spasmodic tetanic involuntary smile)
and trismus (lockjaw), which are early and constant
clinical signs of C. tetani infection.
– Muscles that are close to the site of infection appear
to be more severely affected early on and are the last
to lose their hypertonicity.
MECHANISUM OF ACTION
Site
36. • Violent muscular spasms
• Trismus (lockjaw) due to masseteric spasm is the single
most common early sign.
• Ophisthotonus (Arched back) spasm of extensor of the
neck, back (Spinal muscle spasm) and legs to form
backward curvature
CLINICAL FEATURES
37. • Risus sardonicus / rictus grin (rigid smile) - Facial spasm
produces a so-called sardonic smile in which the eyebrows
are raised with eyes closed and the lips are drawn back
over clenched teeth.
CLINICAL FEATURES
Sardonicus –
skeptically humorous
38. • Spinal muscle spasm produces arching of the back
(opisthotonos),
• Laryngeal spasm can lead to asphyxiation.
• Autonomic dysfunction can cause siezures, cardiac
arrhythmias and fluctuations in blood pressure.
• Death may follow within 10 days of the onset of tetanus,
usually from asphyxia, autonomic dysfunction or
bronchopneumonia.
CLINICAL FEATURES
39. DIFFERENCES BETWEEN
TETANUS TOXIN
• produced by Clostridium tetani
• contaminated and produced by
deep wound
• cardiovascular parameters can
fluctuate widely
• TeNT specifically cleaves VAMP –
Synaptobrevin
• Inhibits the release of inhibitory
neurotransmitter – GABA and
glycine at interneuronal junction
• generalized muscle
spasms (Spastic paralysis)
develops
BOTULINUM TOXIN
• produced by Clostridium
botulinum
• Botulinum neurotoxin is a food
poison. Preformed exotoxin
• cardiovascular parameters
fluctuation is minimal
• BoNT serotypes
– B, D, F and G specifically
cleave VAMP/synaptobrevin.
– A and E cleave SNAP-25
– C is syntaxin
• Inhibits the release of stimulatory
neurotransmitter – acetylcholine
at peripheral nerve endings
• descending flaccid
paralysis occurs
40. • Faith C. Blum, Chen Chen, Abby R. Kroken, Joseph T. Barbieri. 2012.
Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter
Neurons of the Central Nervous System. Infection and Immunity. 1662–
1669
• Salinas S, Schiavo G, remer EJ. 2010. A hitchhiker's guide to the nervous
system: the complex journey of viruses and toxins. Nat. Rev.
Microbiol. 8:645–655
• Yeh FL. 2010. SV2 mediates entry of tetanus neurotoxin into central
neurons. PLoS Pathog.6:e1001207.
• Caleo M, Schiavo G. 2009. Central effects of tetanus and botulinum
neurotoxins. Toxicon 54:593–599.
• R Pellizzari, O Rossetto, G Schiavo, and C Montecucco. 1999. Tetanus and
botulinum neurotoxins: mechanism of action and therapeutic uses. Philos
Trans R Soc Lond B Biol Sci. 354(1381): 259–268.
• https://oncohemakey.com/tetanus-2/
• https://slideplayer.com/slide/12677091/
• https://www.scribd.com/document/27595213/Clostridium-2
• https://en.wikipedia.org/wiki/Tetanospasmin
REFERENCES