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Bacterial Toxins

Any of various microbial products or


components
which,
at
low
concentrations, can act in a specific way
on cells or tissues in a higher
(multicellular) organism and cause local
and/or systemic damage, or death such
an agent (alone, or with other toxin(s)
and/or
virulence
factor(s))
being
responsible, directly or indirectly, for at
least some aspect of pathogenesis.

Not all toxic microbial substances are called


toxins.
Those microbial products which, at low
concentrations, are toxic to other
microorganisms are not Toxins.
Many types of bacterial toxin can induce
cytokines, the exotoxins being particularly
potent inducers.

The definition of a toxin may be based on


criteria which differ in different disciplines.
Thus, medical workers may accept as toxins:
(i) certain microbial enzymes which act as
AGGRESSINS;
(ii) substances toxic to cells in vitro but whose role
in causing or exacerbating disease under natural
conditions is unknown;
(iii) substances produced at a site remote from the
target organism (e.g. BOTULISM).

Direct enzymatic mechanism which effects target


cells.

Facilitate spread through tissues


Damage cell membranes
Immunomodulatory
Inhibit protein synthesis
Inhibit release of neurotransmitters

Single cause for disease or just a contributor


the zinc-endopeptidase activity of tetanus toxin,
which blocks neuroexocytosis.

A given toxin may be categorized according


to:
the nature of the organism producing it (e.g.
mycotoxin, phycotoxin),
the nature of the organism affected by it (e.g.
ichthyotoxin),
the type of cell or tissue affected (e.g.
ENTEROTOXIN, HAEMOLYSIN sense 2,
hepatotoxin, LEUCOCIDIN, NEUROTOXIN) etc.
the method by which it releases (ENDOTOXIN
and EXOTOXIN.)

Bacterial toxins
Exotoxins releases
from the living cell.

Endotoxin part of cell


wall released when
organism dies

Sub-unit (A-B) Toxins


A sub-unit
enzymatic (toxic) activity
Protein synthesis inhibitors
Examples: E. coli LT; cholera toxin; Shiga toxin

Adenylate cyclases
Example: anthrax edema factor

B sub-unit
Mediates binding to host cell receptor.
Host gangliosides (glycolipids) or glycoproteins

Facilitates translocation of A sub-unit.

Diphtheria caused by Corynebacterium diphtheriae


Toxin inhibits protein synthesis in heart muscle & other
cells

Tetanus caused by Clostridium tetani


Toxin affects neuromuscular junctions constant release
of acetyl choline irreversible contraction of muscle and
spastic paralysis

Botulism caused by Clostridium botulinum


Toxin affects neuromuscular junctions prevents release
of acetyl choline lack of stimulus to muscle and flaccid
paralysis

Cholera caused by Vibrio cholerae


Toxin activates adenyl cyclase in intestinal cells
disruption of Na+ influx and loss of water into the lumen
and diarrhoea

Proteolytic Toxins
Zinc metalloendoproteases
Neuropathologic effects
Inhibit release of neurotransmitters
Delivery-dependent disease presentations
Oral, example: Botulinum toxin- causes flaccid
paralysis
Cleaves synaptobrevin to inhibit release of
acetylcholine in peripheral nerves

Immunoglobulin A (IgA) proteases


Made by pathogens that colonize mucosal
surfaces
Examples: Haemophilus, Neisseria, Serratia,
Helicobacter

Unlike some other toxins, does not require


elaborate secretion system - autosecreted
by the bacterium
Specifically cleaves secretory IgA1

Pore-forming Toxins
RTX (repeats-in-toxin) family
Produced by many Gram negative pathogens
Example: E. coli haemolysin

Induce cytolytic effects by insertion into the target cell


membrane

Sulfhydryl-activated family
Produced by Gram positive pathogens
Example: L. monocytogenes Listeriolysin O
Mediates escape from macrophage vacuole
Activity triggered by low pH

Cytolytic toxins
Act on cell membranes
Haemolysins
Leucocidins
Often phospholipases,
lecithinases,
poreforming toxins

CM Toxins
Alter host cell actin filament polymerization
state.
Anti-phagocytic and/or Necrotic effects
Yersinia Outer Proteins (YOPs)
E. coli cytotoxic necrotizing factor I (CNF1)

Enhance cell-cell interactions (example: EPEC)

Pyrogenic Exotoxins

Superantigens
Potent activators of T-cells
Suppress B-cell responses
Enhance susceptibility to LPS
Stimulate cytokine production
Examples:
Staphylococcus enterotoxin B (SEB)
S. aureus toxic shock syndrome toxin

Endotoxins
Lipopolysaccharide from the cell wall of Gram
negative bacteria
Released when organisms die and bacterial
cells are lysed
Cause a variety of effects
Fever, generalised fever, inflammation, circulatory
collapse septic shock

Exotoxin

Endotoxin

composition

protein, often A-B type

lipid A of LPS

disease example

botulism, diphtheria,
tetanus

Gram-neg infect

effect on host

variable

similar

fever

no

yes (IL-1)

genetics

often plasmid or PAI

chromosome

heat stable

no

yes

location

Secreted

part of cell o.m.

toxicity

very high

moderate

toxoid

yes (heat or formaldehyde)

no

Group 1 toxins act either by binding receptors on the


cell membrane and sending a signal to the cell or by
forming pores in the cell membrane, perturbing the
cell permeability barrier.
Group 2 toxins are A/B toxins, composed of a binding
domain (B subunit) and an enzymatically active effector
domain (A subunit). Following receptor binding, the
toxins are internalized and located in endosomes, from
which the A subunit can be transferred directly to the
cytoplasm by using a pH-dependent conformational
change or can be transported to the Golgi and the
endoplasmic reticulum (ER), from which the A subunit
is finally transferred to the cytoplasm.
Group 3 toxins are injected directly from the bacterium
into the cell by a specialized secretion apparatus (type
III or type IV secretion system).