pathogenesis 3: toxin/tissue damage

what are two Primary Classes of Toxins:

endotoxins and exotoxins

endotoxins are…

Lipopolysaccharide of gram negative bacteria

exotoxins are toxins

released from bacteria

what is a unique group of exotoxins 

superantigens

What part of lipopolysaccharide (LPS) is toxic

lipid A component extremely toxic

what is the integral part of outer membrane

Lipopolysaccharides (LPS) of Gram negative bacteria

toxicity from lipopolysaccharides is due to

immune reaction

endotoxins are

embedded

how are endotoxins released

only by lysis

how to kill endotoxins

attack by membrane attack complex

killing by phagocytes

killing by lysis-inducing antibiotics

Exotoxin Categories

1. A-B toxins

2. Membrane-disrupting toxins

3. Proteolytic toxins

4. Superantigens

how are A-B toxins secreted 

by bacteria 

when do A-B toxins become toxic

once they are taken up by host cells

what are two necessary portions of the A-B toxin molecule

A- Active portion

B- Binding portion

A portion 

has toxic or enzymatic activity 

causes damage to the host 

B portion

receptor specificity

-determines host species specificity

-determines host cell specificity

Number of A and B units

varies

For some, B portions

binds to the outside 

• may remain outside 

• the A portion will enter the cell to exert action 

for other B portions.. the

whole molecule may enter

• cleavage releases the active A portion 

A-B toxins work

by many different mechanisms

examples of A-B toxins

Diptheria toxin

Shiga toxin

Tetanus toxins

Botulinum toxins

Diptheria toxin subunit 

Single A and single B

what does the diptheia toxin inactivate

elongation factor-2

what does inhibition of elongation factor-2 stop

protein synthesis

Diphtheria Pseudomembrane

Thick leathery membrane in throat can obstruct patient’s breathing

cholera toxin subunit

Five B and one A moiety, only A1 goes in

what does the cholera toxin modify 

the protein regulating  cAMP synthesis 

what does the accumulation of cAMP do

causes loss of control of ion flow

cholera toxin symptom

Massive watery diarrhea (24+ liters/day)

how to treat cholera toxin

Treat with i.v. fluids

• antibiotics are not always needed 

shiga toxin

not excreted from bacteria

when is the shiga toxin released

when organisms are lysed

what does shiga toxin do

Stops host cell protein synthesis

how does the shiga toxin stop host cell protein synthesis 

cleaves host cell 60S ribosomal RNA

prevents protein elongation

what does the shiga toxin cause

mucosal damage, bloody diarrhea

tetanus toxin motility

Organism rarely moves from site of infection

• but toxin spreads throughout body 

how does the tetanus toxin act

at a distance

• binds and taken into alpha-motor neurons

• travels up axon into spinal cord

what does the tetanus toxin block

release of inhibitory neurotransmitters

tetanus toxin symptoms

Muscles constantly stimulated (tetany)

Membrane-disrupting toxins

Cytotoxins, hemolysins

what do membrane-disrupting toxins disrupt 

the integrity of host cell plasma membranes

how do some Membrane-disrupting toxins enter

insert into membranes to form pores

• no an enzymatic action 

low concentration

inhibit target cell function

higher concentrations can

lyse target cells by osmotic shock

some membrane- disrupting toxins have some

phospholipase activity

what does phospholipase activity do 

remove polar head groups from membrane lipids

what does phospholipase activity do 

destabilization of membrane causes cell lysis

are membrane disrupting toxins more or less type specific than A-B toxins

often less- membrane targets are found on many cells 

what are proteolytic toxins

enzymes

what do Proteolytic Toxins properties

Facilitate invasion or provide nutrients

Proteolytic Toxins do

cut antibodies or parts of host complement system

Proteolytic Toxins are

“Spreading factors” aid in tissue invasion

are superantigens enzymes?

no they are not enzymes

what are superantigens

Potent polyclonal stimulators of T-cell activation and proliferation

superantigens Nonspecifically

bind helper T-cells to antigen-presenting cells

what do superantigens cause

excessive proinflammatory cytokine production

super antigens symptoms

Fever, vomiting, malaise, shock

superantigens sequence

bind antigen-presenting cells to T cells causing the overproduction of proinflammatory signals to the immune system

t- cell activation

release of large amounts of cytokines

t-cell activation symptoms

life-threatening fever, shock, rash, and autoimmune-like responses.

exotoxins benefit to the pathogen/bacteria

killing host defense cells

obtain nutrients from host cells or tissues

help in dissemination

where are exotoxins produced

both by Gram + and Gram - bacteria

exotoxins are what type of molecule

protein 

protein molecule properties 

heat labile & very potent

usually can be “detoxified” by heat

• can be used as a vaccine 

how do most exotoxins act

enzymatically

act enzymatically

destroy host tissues

destroy host cells (lyse or stop cell growth)

alter cell function (depress or amplify)

many exotoxins are

plasmid or phage encoded

what is exotoxins production regulated by

grwoth conditions or host signals

some exotoxins can be made into

effective “toxoids”

• alter function, but retain antigenicity

host response to low concentration LPS

produce alarm reaction

low concentration symptoms

Fever due to IL-1 an TNFα release by macrophages

Complement activation = Inflammation

Lymphocyte activation leading to antibody synthesis

high concentration host response to LPS

Septic shock

Severe hypotension

Clotting factors released

Disseminated intravascular coagulation (DIC)

Multi-organ system failure, ARDS