ii. A Focus on Bacterial Toxins Flashcards
A Focus on Bacterial Toxins.
What is the background? (3)
- Diphtheria toxin was isolated by Roux and Yersin in 1888
- Primary virulence factor for a variety of pathogenic bacteria
- Toxic production was the first recognised pathogenic mechanism in bacterial infection and resulted in early successful therapeutic and preventative measures
What is toxins?
- TOXINS: Soluble substances that alter the normal metabolism of host cells with deleterious effects on the host.
What are toxoids?
- TOXOIDS: Inactive toxins used as vaccines. Detoxified
toxins which retain their antigenicity and immunogenicity capacity.
Toxins may be treated with a variety of reagents – Formalin, Iodine, Ascorbic acid, Ketones etc. to form toxoids. For many bacterial infections, part or all of the characteristic pathology of the disease is caused by toxins.
Diptheria and tetanus toxins represent sole determinants of disease and are neutralized by specific antitoxin antibody. As a result, vaccination with toxoid derived from these toxins is highly effective.
What is an endotoxin? (2)
- Term “endotoxin” was originally introduced to describe the components of gram-negative bacteria responsible for the pathophysiology of endotoxic shock.
- Produced only by gram negative bacteria
Properties: Endotoxins - Lipopolysaccharide/Lipooligosaccharide
What are the features of endotoxins? (3)
- Endotoxins are a component of the gram-negative cell wall
- The action of endotoxin requires the presence of the bacteria in the host.
- The endotoxin may be released from the cell wall as the cells die and disintegrate (as outer
membrane vesicles).
What is an endotoxin composed of?
- Endotoxin is composed of Lipid A: Part of the lipopolysaccharide layer
Lipopolysaccharide is anchored in the bacterial outer membrane through Lipid A. Covalently linked to lipid A is an 8-carbon sugar which is in turn linked to a chain of sugar molecules that form the highly variable O-antigen specific side chain of gram-negative bacteria.
What is the mode of action of an endotoxin?
- Mode of action: Irritation/inflammation of epithelium, GI irritation, capillary/blood vessel inflammation, haemorrhaging.
What are exotoxins secreted into?
- Is secreted into the external medium by the bacteria. Most pathogens secrete various diffusible protein molecules that facilitate adhesion to or invasion of the host. Many others cause damage to host cells. Toxins vary in molecular structure, biological function, mechanism of secretion and immunological properties.
What are exotoxins produced by?
- May be produced by either Gram-positive or Gram-negative bacteria
Exotoxins - Properties:
- Most of protein toxins are thought of as exotoxins since they are released from the ______ and act on the host cells at a distant site.
- The action of the exotoxin does not necessarily require the presence of the bacteria in the host
- Most exotoxins are _____ or protein
- Most exotoxins are ____ sensitive (Exception: Enterotoxin of Staphylococcus aureus)
bacteria
peptide
heat
- Classes of exotoxins: (3)
o Neurotoxins: Interfere with proper synaptic transmissions in neurons
o Cytotoxins: Inhibit specific cellular activities, such as protein synthesis
o Enterotoxins: Interfere with water reabsorption in the large intestine; irritate the lining of the gastrointestinal tract.
Mode of action of bacterial toxins: (5)
- Damage cell membrane
- Inhibit protein synthesis
- Activate second messenger pathways
- Inhibit the release of neurotransmitters
- Activate host immune response
How do bacterial toxins damage membranes? (3)
How does the S. aureus alpha Toxin initiate toxin?
Damage to cellular membranes by S. aureus a-toxin. After binding and oligomerization, the stem of the mushroom shaped toxin heptamer inserts into the target cell and disrupts membrane permeability as depicted by the influx and efflux of ions (red and green circles)
How is protein synthesis inhibited? (2)
- Substrates for toxins in this group are elongation factors and ribosomal RNA.
- Inhibition results in cell death.
What is the - AB-toxin structure? (2)
- AB-toxin structure: An enzymatically active (A) subunit is noncovalently associated with a
binding component (B) - Inhibition of protein synthesis by Shiga toxins Stx
The AB-toxin enters cells through the globotriasylceramide (Gb3)
The N-glycosidase activity of the A subunit cleaves an adenosine residue from the 28S ribosomal RNA which halts protein synthesis.
Other toxins that share the same structure are E.coli and cholerae,
Rho family of GTPases:
- Roles include:
- Roles include: Organelle development,
cytoskeletal dynamics, cell movement, and other common cellular functions
Inhibit the release of neurotransmitters:
- Neurotoxins: (2)
o Clostridium botulinum toxins - Infants and foodborne botulism, found in large complexes in nature with proteins that provides protection/stability.
o Clostridium tetanus toxin (tetanospasmin) - Synthesized from vegetative C. tetani (spores) in wounds, unbound (doesn’t form complexes with any other protein component).
- Contrasting clinical manifestations of C. butilinum and C. tetani neurototoxins intoxication, ____ VS ____ paralysis, is the direct result of the specific neurons affected and the type of neurotransmitters being blocked.
flaccid
spastic
T-cell response
Conventional response:
Superantigen response:
- Small proportion of T- cells activated, highly regulated
- Massive T-cell activation (20-30%), associated with adverse consequences
