bacterial toxins Flashcards
toxins
there’s a huge diversity of toxins
loads of different bacteria produce toxins. They have different mechanisms of action. They act on different cell types and they act on different targets within cells.
- you can roughly split them into non-protein toxins and protein toxins
non protein toxins
endotoxin; embedded in the cell surface
and the term endotoxin is specific for lipopolysaccharide, which is in the outer membrane of gram-negative bacteria.
You do have other bacterial cell wall components that can have the same effect of endotoxin e.g lipoteichoic acid and phosphatidylglycerol
mycolactone - non protein toxin
The only other non-protein toxin that’s been characterized is something called mycolactone and this is a polyketide derived drug molecule and this is produced by some mycobacteria.
- this toxin is responsible for this disease called buruli ulcer, which is where you get Progressive necrosis on the skin.
- So you get this necrosis due to the toxin causing tissue damage, but actually the bacteria remain localized So actually it’s very Superficial on the surface,
- this disease isn’t really seen outside the tropics but it’s recently been registered as an emerging disease in West Africa.
protein toxins
there’s three different types of protein toxins
- huge diversity and they’ve just been roughly divided into three groups
○ type 1 type 2 type 3.
- So the protein toxins are known as exotoxins because these get released from the bacterial cell.
endotoxin characteristics
chemical nature: lipopolysaccharide
relationship to cell: part of outer membrane
denatured by boiling: no
antigenic: yes
form toxoid: No
potency: relatively low (<100 micrograms)
specificity: low degree
enzymatic activity: no
pyrogenicity: yes
exotoxin characteristics
chemical nature: protein
relationship to cell: extracellular, diffusible
denatured by boiling: usually
antigenic: yes
form toxoid: yes - important in vaccines
potency: relatively high (1 micrograms)
specificity: high degree
enzymatic activity: usually
pyrogenicity: occasionally
the inflammatory response
endotoxin triggers inflammation that can lead to septic shock
inflammatory response involves 4 main events:
- vasodilation
- activation of endothelial cells
- increased vascular permeability
- chemotactic factors
brought out by combination of complement activation, cytokine release, monocyte and PMN transmigration/ activation
inflammatory response - activation of endothelial cells
It makes them sticky so neutrophils and other cells start to stick to them and that helps with them starting to move out of the blood vessels into tissues
inflammatory response - increased vascular permeability
This helps neutrophils squeeze through the gaps between the endothelial cells and also helps things like complement move out of the bloodstream into the tissue
inflammatory response - chemotactic factors
drive the neutrophils macrophages et cetera to the site of infection and obviously complement factors play a key role with chemotaxis
symptoms of inflammation
you get heat with inflammation and that’s due to the increased blood flow to the area
Get redness
Then you start to get swelling and the swelling is due to a buildup of fluid in the area.
pain is due to pressure on nerve ending
then eventually you get loss of control and that can be devastating if it’s this systemic inflammation.
stages of septic shock
- systemic inflammatory response syndrome
- sepsis
- severe sepsis
- septic shock
1st stage of septic shock - systemic inflammatory response syndrome
- temperature over 38 or less than 36
- higher than normal respiratory rate
- usually high neutrophil count
- mild hypotension
all of this can be brought about by one thing which is endotoxin
septic shock - stage 2 (sepsis)
SIRS with proof bacteria in bloodstream
sepic shock - sever sepsis - stage 3
- multiple organ dysfunction
- dramatic hypotension - the fluid is moving out of the bloodstream into the tissues
septic shock - stage 4
- hypotension despite fluid administration
- disseminated intravascular coagulation
- acute respiratory distress
- multiple organ failure and death
relationship between bacterial endotoxin structure, function and biological activity
in terms of variability, there’s a very low variability of lipid A between different bacteria.
No variability of the diphosphate
and then as you move out you get more and more variability. - O antigen variability high
in terms of endotoxin activity. It’s the lipid a component that causes the activity
- so the lipid a is essential because that’s integral within the bacterial membrane.
-the lipid A is a component within the outer membrane, that’s somehow got to be released for it to have an effect -So it’s due to lysis of the bacteria that you get this effect of endotoxins
structure of bacterial endotoxin (LPS)
O - antigen
core polysaccharide
disaccharide diphosphate
lipid A
fatty acids
how does endotoxin trigger septic shock (1)
- You get bacterial lysis, so that will release the LPS and then that gets Bound in the serum by LPS binding protein.
- they form a complex and then that Bind to the receptor cd14 on phagocytes
- Once cd14 is associated with LPS and LPS binding protein that triggers TLR 4 to start signalling Pathways, and that causes cytokine release
- And then that’s what has the effect.
if it is all localized. It’s no problem and is beneficial to fight an infection but it’s when it happens systematically It’s an issue.
septic shock - activation of complement pathway (2)
- So All of this in the release of acute phase proteins cause activation of complement Cascade- you get production of prostaglandins and leukotrienes- and you also get activation of the coagulation Cascade
- and in terms of symptoms you start to see acute respiratory distress syndrome due to activation of the coagulation Cascade and you get this disseminated intravascular coagulation.
so you start to get endothelial damage and then that might lead to multiple organ failure
- and in terms of symptoms you start to see acute respiratory distress syndrome due to activation of the coagulation Cascade and you get this disseminated intravascular coagulation.
exotoxins - cytotoxins
attack a variety of cell types
- toxins that attach specific cell types include: neurotoxin, leuokotoxin, hepatotoxin, cardiotoxin
exotoxins - cholera toxin
produced by vibrio cholerae
exotoxins - shiga toxin
produced by shigella species
exotoxin - diptheria toxin
produced by corynebacterium diptheriae
exotoxin - tetanus toxin
produced by clostridium tetani
exotoxin - adenylate cyclase
toxin produced by bordatella pertussis cause of whooping cough
exotoxin - phospholipase
toxin produced by clostridium perfringens cause of gangrene
exotoxin - enterotoxin
protein toxins that cause diarrhea or vomiting
exotoxins - type 1
superantigens - toxins that get released from a bacterial cell, They bind to host cell surfaces, but they don’t go into the host cells.
- antigen-independent activation of T cells
- inappropriate activation of IL-2 -> toxic shock
symptoms identical to septic shock. It’s just been induced by a different mechanism.
exotoxins - type 2 toxins
pore-forming, phospholipase
- destroy the integrity of the mammalian cell cytoplasmic membrane
exotoxins - type 3 toxins
A-B toxins
- have a B portion comprising a translocation (T) domain and a receptor binding domain (R)
- have an enzymatic portion (A) that acts on some intracellular host protein
how do type 1 toxins work
super antigens bind indiscriminately to MHC Class 2 and CD4 T cell receptors and forms a link between the two that doesn’t require an antigen to be present.
- So this means now that almost any CD4 T cell can become activated - It doesn’t have to have the right receptor
- so you get up to one in five T cells can be activated in this way.
- this then causes the clonal expansion of the huge diversity of CD4 T-cells and a huge diversity of receptors and you get an unfocused immune response
- you get an excess production of cytokines and then that leads to systemic Inflammatory response and you get toxic shock.
normal antigens mechanism
normally when an antigen presenting cell like a macrophage expresses an antigen on the surface for recognition by CD4 T-cells, it presents that antigen on MHC Class 2.
- And so then that gets recognized by CD4 T cells that have the specific receptor for that antigen
- , so then those CD4 T cells become activated and they start to proliferate and you get the production of cytokines.
- So when this happens normally it’s only the CD4 cells with the right receptor for that antigen - so it’s about one in 10,000 CD4 T-cells that becomes activated.
examples of superantigen - toxic shock syndrome toxin-1
- superantigen produced by some strains of staphylococcus aureus
- causes toxic shock syndrome
examples of superantigen - staphyloccal enterotxins
- superantigens produced by some strains of staphylococcus aureus
- cause food poisoning
examples of superantigen - streptococcal pyrogenic exotoxin
- produced by group A streptococci
- causes toxic shock-like syndrome
type 2 toxins action - pore-forming toxins
- insert into host cell membranes And they form a pore in the membrane.
- That pore causes an ion imbalance because of the difference in osmolarity.
- So ions rush out, water rushes in and the cell bursts.
- the pore-forming toxins usually associate with cholesterol in the cell membrane
a big difference between the cell membrane of bacteria And host cells is the presence of cholesterol in the host cells so that’s why they’re specific for the host cell membranes and don’t affect their own membranes.
type 2 toxins actions - phospholipase
- they cleave the phospholipids in the bilayer.
- they disrupt the membrane and that causes membrane damage and can cause the cell to lyse
exmaples of type 2. toxins - pore forming
staphylococcal alpha-toxin
- produced by staphylococcus aureus
- pore-forming cytolysin
listeriolysin
- produced by listeria monocytogenes
- pore-forming membrane damaging toxin, role in mediating escape from phagosome
pneumolysin
- produced by streptococcus pneumoniae
- pore forming cytolysin
- induction of inflammation in lung
- inhibits cilial beat in respiratory mucosa
exmaples of type 2. toxins - phospholipase
clostridium perfringens alpha toxin
- causes gas gangrene
- demonecrotic and hemolytic
- is a zinc metallophospholipase C
gas gangrene
results from toxin and gas production during anaerobic fermentation
type 3 toxins types
- simple A-B toxin
- compound A-B toxin
