4.1 Toxins (not diseases) Why This Much ?? Shorten It !! Flashcards
What is toxigenesis ?
ability to produce toxins
What type of toxins may bacteria produce ?
- exotoxins
- endotoxins
- where are exotoxins released from ?
- exotoxins may act on what ?
- bacterial cells
- tissue sites removed from the site of bacterial growth
What type of substances are endotoxins ?
cell-associated
Difference between gram positive and gram negative bacteria ?
Gram positive
* thick layer of peptidoglycan
* no outer membrane
* no lipopolysaccharide
* stains blue/purple on gram stain
* S. aureus, Streptococci
Gram negative
* thin layer of peptidoglycan
* presence of outer membrane
* presence of LPS
* stains pink/red on gram stain
* E.coli, salmonella spp
Example of an endotoxin
Lipopolysaccharide (LPS) on surface of bacterial cell of gram negative bacteria
When are LPS endotoxins released from Gram negative bacteria ?
- after destruction of the bacterial outer membrane
- secreted in bacterial vesicles
Why can LPS (endotoxins) be transported around the body via lymph or blood ?
because LPS is released after destruction of the bacterial outer membrane or secreted in bacterial vesicles
How can endotoxin (LPS) be transported around the body ?
lymph or blood
As endotoxins are exposed on the surface of bacteria, what has the inante immune system done to evolve ?
to recognise them as a threat and to react accordinly to their presence
Why do endotoxins provoke a strong innate immune response ?
they are pyrogens
Name the toxic componenet of endotoxins
Lipid A
What is the immune response against Lipid A mediated by ? Which expressed on what ?
TLR4 expressed on myeloid cells (e.g. macrophages)
What does TLR4 stimulate the secretion of what from macrophage and endothelial cells ?
Macrophage -> pro-inflammatory cytokines
endothelial cells -> nitric oxide
- In macrophages and monocytes what do endotoxins trigger ?
- and consequent release of what ?
- production of inflammatory cytokines
- prostaglandins
List some of the inflammatory cytokines produced by macrophages and monocytes upon being triggered by endotoxins
- IL-1
- IL-6
- IL-8
- TNF
- platelet-activating factor
- LPS endotoxins stimulates which 2 cascades ?
- Inducing what ?
- complement & coagulation cascades
- inflammation , vasodilation, chemotaxis of neutrophils, coagulation , bleeding and shock
[change Q!] In the normal host response the pro-inflammatory response (as an effect of endotoxins) is regulated and localised by what ?
a simultaneous anti-inflammatory response
List 4 effects of endotoxin
Activation of 3 …. And release of…
- macrophage activation
- release of TNF-alpha
- complement activation
- tissue factor activation
what is released in macrophage activation - as an effect of endotoxins ?
- release of IL-1 and IL-6 (proinflammatory cytokines), responsible for fever (prostaglandins)
Explain the effect of endotoxin - release of TNF-alpha
- fever
- release of nitric oxide
- hypotension
As an effect of endotoxins, the complement activation is involved to release C5a and C3a what are there separate effects ?
C5a - neutrophil chemotaxis
C3a:
histamine release
causing hypotension
odema
Explain the effect of endotoxin - tissue factor activation:
Activates … results in ….
- activates coagulation cascade
- results in disseminated intravascular coagulation
How does LPS produce an inflammatory response ?
- Lipid A stimulates TLR-4 expressed on myeloid cells (e.g. macrophages)
- TLR-4 stimulation leads to production of pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-8, TNF & platelet-activating factor)
- also stimulate production of prostaglandins
- complement and coagulation cascades are activated
- Inducing inflammation , vasodilation , chemotaxis of neutrophils, coagulation , bleeding & shock
- What is sepsis characterised by ?
- due to presence of what ?
- complex systemic inflammatory response
- microorganisms in the bloodstream
What are the leading causes of severe sepsis ? Give 2 examples
Gram negative bacteria
* Escherichia coli
* Pseudomonas aeruginosa
Exaggerated inflammation triggered by TLR4 during infection can lead to …?
sepsis and septic shock
Endotoxins:
* ..1… the immune system (TLR4) and is a pyrogen
* Induces massive production of …2… such as TNF-alpha leading to ..3… injuries and ….4.. failure
- activates
- proinflammatory cytokines
- inflammatory tissue
- multiorgan
What are exotoxins a group of ?
soluble proteins that are secreted by the bacterium
What effect do exotoxins have on cells ?
- destroy cells directly
- disrupt normall cellular metabolism
2 examples of exotoxins
- botulinium toxin
- tetanospasmin toxin
What do Type I exotoxins bind to and stimulate ?
bind to receptors on the cell surface and stimulate intracellular signalling pathways
- Example of type I exotoxin
- leading to what ?
- superantigens bind to MHC Class II on T cells
- leading to massive secretion of proinflammatory cytokines(Toxic Shock Syndrome by S. aureus/ S. pyogenes)
Type II exotoxins are membrane ….1… which can either form ….2.. in the target cell membrane or …3.. that act on the ..4…
- damaging
- pores
- enzymes
- membrane
Example of type II exotoxin = ..1.. released by Streptococcus pneumoniae triggers direct …2… of ..3.. epithelium and nasal …4…. epithelium (penumonia , pneumococcal invasive disease)
- pneumolysin
- cytotoxicity
- lung
- tracheobronchial
Type III exotoxins = ..1… toxins which gain access to ….2.. of target cell to exert effects
- intracellular AB
- cytoplasm
Type III exotoxin example = …1… toxin enters the ..2.. and stimulates ..3… of chloride ions pumped ….4.. the cell (Vibrio …5.., …6..)
- cholera
- cell
- ATP mediated efflux
- out of
- cholerae
- cholera
Enterotoxin:
1. act on ?
2. cause ?
- GI tract
- diarrhoea
neurotoxins:
1. act on ?
2. cause ?
- nerves or neuromuscular junction
- paralysis
pyrogenic exotoxins:
1. stimulate?
- release of cytokines
what do tissue invasive exotoxins do to invade the host ?
enzymes destroy tissue
Difference in species between exotoxin and endotoxin ?
Exo = some species of both Gram positive and gram negative
Endo = most gram-negative bacteria and Listeria
Difference in protein location between exotoxin and endotoxin ?
Exo = proteins secreted from cell
Endo = part of cell (lipopolysaccharide) that fragments off
Difference in gene location between exotoxin and endotoxin ?
Exo = in plasmid or bacteriophage
Endo = on bacterial chromosome
Difference in toxicity between exotoxin and endotoxin ?
exo = high toxicity
endo = low toxicity
Difference in antigenicity between exotoxin and endotoxin ?
exo = highly antigenic (host forms antibodies called antitoxins)
endo = poorly antigenic
Difference in availability of vaccine between exotoxin and endotoxin ?
exo = vaccine available (formed from toxoids)
endo = no vaccine available
Difference in heat stability between exotoxin and endotoxin ?
exo = heat labile (sensitive)
endo = heat stable (resistent to effect)
Difference in examples between exotoxin and endotoxin ?
exo = cholera, tetanus, botulism
endo = meningococcemia , sepsis
Toxins can cause disease in various ways , list 4 ways this includes:
- overstimulation of immune response
- cytotoxicity
- apoptosis
- disruption of cell function
List 4 disease mediated by toxins
- botulism
- tetanus
- cholera
- necrotising fasciitis
List 4 examples of toxins
- cholera toxin
- tetanospasmin
- botulinium neurotoxin
- M protein
