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THE BACTERIA
Soluble Toxins
Table of Contents
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Educational Objectives
Extracellularly-Acting Toxins
Intracellular-Acting Toxins
Summary
While the bacterial cell may be composed of entities that are toxic; e.g., lipid A, a
greater variety of toxins are synthesized and released from the cell in soluble form.
These are the exotoxins.
Educational Objectives
General
1.
To develop an understanding of the role of exotoxins in infectious disease.
2.
To emphasize the uniqueness of the bacterial exoenzymes.
3.
To define the mode of action of bacterial exoenzymes.
Specific (terms and concepts upon which you will be tested)
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ADP-ribosyl transferase
Adenylate cyclase
Alpha toxin
Anthrax toxin
toxin
Botulinum toxin
Cholera toxin
Clinical results of toxemia
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Coagulase
Collagenase
Cysteine protease
Diphtheria toxin
Erythrogenic toxin
Exfoliating toxin
Exoenzyme S
Exotoxin A
Fibrinolysin
Hemolysin
Hyaluronidase
IgA protease
Labile toxin (LT)
Lecithinase
Leukocidin
Lipase
Modes of action of toxins
Mycolactone
NAD glycohydrolase
Pertussis toxin
Phospholipase
Pyocyanin
Shiga toxin
Spreading factor
Tetanus toxin
Toxic shock syndrome toxin
Extracellularly-Acting Toxins
Non-Membrane Damaging
1. Hyaluronidase - This is also called the spreading factor because it catalyzes the
breakdown of hyaluronic acid, the
substance that cements the human cells together. This allows the bacterial cells
to spread through tissue causing a
condition known as cellulitis.
2. Coagulase- This enzyme catalyzes the conversion of fibrinogen to fibrin with
resultant clot formation.
3. Fibrinolysin - This catalyzes the conversion of plasminogen to the fibrinolytic
enzyme plasmin. Thus it acts
opposite of coagulase. In Staphylococcus aureus, the gene for fibrinolysin is on a
bacteriophage and is expressed
during lysogeny.
4. Lipase - Production of excessive amounts of lipase allow bacteria to penetrate fatty
tissue with the consequent
formation of abscesses.
5. IgA protease - Many bacteria which colonize the mucous membranes produce an IgA
protease which degrades
secretory IgA.
6. Collagenase- This enzyme catalyzes the degradation of collagen, a scleroprotein
found in tendons, nails and hair.
Membrane Damaging
1. Hemolysins - There are many different types of hemolysins but, in each case, the
end result is lysis of the red
blood cell with resultant anemia.
2. Leukocidins- Again, there are many different types of leukocidins, and some are
specific for only one type of
leukocyte. However, the end result in lysis of leukocytes with resultant
leukopenia.
3.Phospholipase- This enzyme attacks any cell with phospholipid in its membrane. The
result is widespread cell
lysis. Lecithinase - (phospholipase C) is an enzyme which breaks down the
lecithin in the human cell plasma
membrane, resulting in cell lysis. It is especially active on red blood cells. It is also
called a toxin.
Intracellular-Acting
ADP-ribosyl transferases
These promote the breakdown of nicotinamide adenine dinucleotide (NAD) into
nicotinamide and adenine diphosphate ribose (ADPR) and the covalent binding of the
ADPR to various proteins, thus inactivating the bound protein.
1. Diphtheria toxin. Corynebacterium diphtheriae cells lysogenized with the -phage
produce a diphtheria toxin
which is a bipartite molecule, composed of a B subunit which mediates binding to
a specific human cell surface
receptor and an A subunit which possesses enzymatic (ADP-ribosyltransferase)
activity. The substrate of the
reaction is human elongation factor 2 (EF2), an essential part of the protein
synthetic machinery.
diphtheria toxin
EF2 + NAD -----------------------------> ADPR-EF2 + nicotinamide + H+
The result of this reaction is inhibition of protein synthesis and cell death.
2. Pseudomonas aeruginosa exotoxin A. This works in the same manner as diphtheria
toxin, i.e., it catalyzes the
ADP-ribosylation of EF-2. Human epithelial cell death occurs.
Mode of action of exotoxin A.
A. Exotoxin A, composed of fragments A and B, inhibits eukaryotic cell protein synthesis by
binding to specific receptors
in the cell membrane.
B. After fragment B binds to a cell receptor, fragment A enters the cell.
C. Fragment A catalyzes the binding of nicotinamide adenine dinucleotide (NAD) to Elongation
Factor 2 (EF2), which is
required for translocation of nascent polypeptide chains on eukaryotic ribosomes.
D and E. The reaction terminates in the irreversible formation of an adenosine diphosphate ribose.
EF2 diphosphate -- EF2 complex with
the release of nicotinamide and hydrogen.
3. Pseudomonas aeruginosa exoenzyme S. This is an ADP-ribosyl transferase whose
substrate is unknown. However
EF-2 is not the substrate. It also causes human epithelial cell death.
4. Cholera toxin. Vibrio cholerae growing in the intestine secretes an exotoxin
composed of 5 B subunits, an A
subunit and an A2 subunit. On exposure to small bowel epithelial cells, each B
subunit binds to a receptor on the
gut epithelium. Following binding the A and A2 moieties migrate through the
epithelial cell membrane. The A
subunit is an ADP-ribosyl transferase that catalyzes the transfer of ADPR from
NAD to a guanosine triphosphate
(GTP)-binding protein that regulates adenylate cyclase activity. The ADPribosylation of GTP binding protein
inhibits the GTP turnoff reaction and causes a sustained increase in adenylate
cyclase activity which results in
excess secretion of isotonic fluid into the intestine with resulting diarrhea.
5. Labile toxin (LT) of Escherichia coli. This toxin is identical to that of cholera toxin.
The ability to produce it is
mediated by a plasmid.
6. Bordetella pertussis toxin. During an episode of whooping cough, the B. pertussis
cell produces an exotoxin
composed of an A portion and 4 B portions. The A subunit is an ADP-ribosyl
transferase which elevates
cAMP but in a way different from cholera toxin. It ribosylates a 41,000 MW
membrane protein which specifically
binds guanine nucleotide (the G1 protein).
Non-Ribosylating Toxins
1. Shiga toxin. Species of Shigella carry the gene for shiga toxin on the chromosome.
This toxin has an A subunit
and 5 B subunits. The A subunit can be divided into A1 and A2 subunits. The A1
moiety binds to the 60S human
ribosome which inhibits protein synthesis. The toxin has a multiplicity of effects;
it is neurotoxic, cytotoxic and
enterotoxic.
2. Anthrax toxin. Bacillus anthracis produces an exotoxin composed of three distinct
proteins: protective antigen,
edema factor and lethal factor. The protective antigen is the binding protein, the
edema factor is an adenyl
cyclase and the lethal factor has an unknown function but is thought to be
enzymatic. Dermal necrosis is the result
of the toxin action.
3. Tetanus toxin. Clostridium tetani produces an endopeptidase that cleaves
synaptobrevins: this interferes with
vesicle formation at the myoneural junction and the neural-neural junction in the
spinal cord. The result is muscle
spasm. The tetanus toxin serologically cross-reacts with the botulinum toxin.
A. Neurotransmission is controlled by the balance between excitatory and inhibitory
neurotransmitters.
B. The inhibitory neurotransmitters (e.g., GABA, glycine) prevent depolarization of the
postsynaptic membrane and conduction of the
electrical signal.
C. Tetanospasmin does not interfere with production or storage of GABA or glycine, but rather
their release (presynaptic activity).
D. In the absence of inhibitory neurotransmitters, excitation of the neuroaxon is unrestrained.
4. Botulinum toxin. Clostridium botulinum produces an endopeptidase that blocks the
release of acetylcholine at the
myoneural junction. Muscle paralysis is the result. the botulinum toxin, like
tetanus toxin, cleaves synaptobrevin
thus interfering with vesicle formation. This toxin is used clinically in the
treatment of dystonias.
5. Pyocyanin. Pseudomonas aeruginosa produces this non-enzyme protein which
binds to the flavoproteins of the
cytochrome system. It interferes with terminal electron transport causing an
energy deficit and cell death.
6. Adenylate cyclase. Bordetella pertussis produces a calmodulin-independent
adenylate cyclase which inhibits
and/or kills white blood cells.
7. NAD glycohydrolase. Shigella flexneri, upon being phagocytized, produces a NAD
glycohydrolase which rapidly
depletes the phagocyte of NAD, thus blocking cellular metabolism and bacterial
cell killing.
Toxins with Undefined Mechanism of Action
1.
Trachea toxin. Bordetella pertussis tracheal cytotoxin kills cilia-bearing cells.
2. -toxin. Clostridium difficile produces a beta toxin which causes a necrotic
enteritis.
3. Exfoliating toxin. Staphylococcus aureus produces an exfoliating toxin which
causes a sloughing of skin (scalded
skin syndrome).
4. Toxic shock syndrome toxin. Staphylococcus aureus produces this toxin which
has an undefined mode of action but
is mediated through induction of interleukin-1. It causes hypotension, rash, fever
and desquamation of skin.
5. Erythrogenic toxin. Streptococcus pyogenes produces this toxin which is similar
to toxic shock syndrome toxin.
6. Mycolactone. Mycobacterium ulcerans produces this toxin which causes skin and
muscle necrosis.
Summary
1.
Cellulitis is caused by bacteria producing hyaluronidase, the spreading factor.
2.
Clot formation is caused by bacteria producing coagulase.
3.
Clot dissolution is caused by bacteria producing fibrinolysin.
4.
Abscess formation is caused by bacteria producing lipase.
5.
Bacterial resistance to IgA is mediated by bacterial production of IgA protease.
6. Degradation of hair, nails and tendons is promoted by bacteria producing
collagenase.
7.
Anemia may be the result of bacteria producing hemolysin or phospholipase.
8.
Leukopenia may be due to bacteria producing leukocidins.
9. Many bacteria produce a toxin, ADP-ribosyl transferase, that promotes the transfer
of adenine diphosphate ribose from nicotinamide adenine dinucleotide (NAD) to
various proteins, thus inactivating those proteins. Toxins acting in this way include
the diphtheria toxin, Pseudomonas aeruginosa exotoxin A and exoenzyme S, Cholera
toxin, Escherichia coli labile toxin and whooping cough toxin.
10. Shiga toxin binds to the 60S portion of the human ribosome causing neurotoxic,
cytotoxic and enterotoxic effects.
11.
Anthrax toxin causes dermal necrosis.
12. Tetanus toxin blocks the release of cholinesterase at the myoneural junction,
thus causing muscle spasm.
13. Botulinum toxin blocks the release of acetylcholine at the myoneural junction,
thus causing muscle flaccidity.
14. Pyocyanin produced by P. aeruginosa binds to human cell flavoprotein, thus
blocking electron transport via the cytochrome system.
15. Bordetella pertussis produces an adenylate cyclase which inhibits and/or kills
white blood cells.
16. Shigella flexneri produces a NAD glycohydrolase which destroys human cell NAD,
thus blocking cellular
metabolism.
17. Staphylococcus aureus produces an exfoliating toxin and a toxic shock syndrome
toxin which cause desquamation of skin.
18. Streptococcus pyogenes produces an erythrogenic toxin similar to the toxic shock
syndrome toxin of S. aureus.
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