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Frontiers in infectious diseases > 2. How bacterial toxins contribute to disease and dissemination > Flashcards

2. How bacterial toxins contribute to disease and dissemination Flashcards

1
Q

What are bacterial toxins?

A

Bacterial toxins are substances that are release or secreted from the bacterium that cause damage to the host and are generally regarded as critical in disease progression.

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2
Q

What processes are bacterial toxins involved in?

A
  1. Nutrient acquisition
  2. Disease transmission
  3. Immune evasion
  4. Competition
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3
Q

How are bacterial toxins involved in nutrient acquisition?

A
  1. Some bacterial toxins can break down RBC
  2. The bacteria can then use the haemoglobin as nutrients.
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4
Q

How are bacterial toxins involved in disease transmission?

A
  1. Toxins in necrotic tissue can break out when nutrients are low.
  2. This allows transmission.
  3. Done through things like pus
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5
Q

How are bacterial toxins involved in immune evasion?

A

They can target and eliminate specific immune cells.

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6
Q

How are bacterial toxins involved in competition?

A
  1. Competition with bacteria in the environment.
  2. Compete for resources etc
  3. By killing or inhibiting other bacteria.
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7
Q

What are the 2 main types of bacterial toxins?

A
  1. Endotoxin
  2. Exotoxins
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8
Q

What are endotoxin?

A
  1. Lipopolysaccharides (LPS).
  2. They are components of the gram-negative cell wall that is vital to its integrity.
  3. LPS is released during division but more significantly on bacterial death.
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9
Q

What is the structure of LPS?

A
  1. The O-antigen which is highly variable due to exposure to the immune system and needing to evade detection.
  2. The Lipid A domain which is highly conversed and linked into the membrane. It is highly conserved, and its length determines endotoxicity.
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10
Q

What can LPS trigger in the host?

A
  1. LPS is relatively non-specific and can trigger inflammatory reactions.
  2. TLR4 and others can detect LPS and trigger inflammation through NFkB and IRF3 leading to pro-inflammatory cytokine expression.
  3. LPS can activate the complement, which can trigger inflammation via C5a binding to macrophages.
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11
Q

Why don’t bacteria want to kill the host?

A

Bacteria cannot transmit from dead hosts so killing the host is an evolutionary dead end.

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12
Q

What are the potential contributions of LPS to disease?

A
  1. Immune dysregulation - If LPS activates the immune system does it change the normal function?
  2. Take one for the team - does immune dysregulation by LPS cause other bacteria to survive better.
  3. Accidental side effect - The immune system recognises PAMPs, and our bodies could have evolved to be sensitive to LPS and cause excess inflammation.
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13
Q

What are exotoxins?

A

Toxins actively secreted from the bacteria.

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14
Q

How can exotoxins be classified?

A

By
1. Target/binding site
2. Mode of action
3. Structure
4. Generic function

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15
Q

What is streptolysin O?

A
  1. Produced by streptococcus
  2. Binds to cholesterol
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16
Q

What is diphtheria toxin?

A
  1. Produced by diphtheria
  2. Binds to elongation factor 2
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17
Q

What is cholera toxin?

A
  1. an ADP-ribosyltransferase
  2. Impacts protein synthesis causing cell death.
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18
Q

What is alpha haemolysin?

A
  1. ß-barrel pore forming toxin
  2. Produced by S. aureus.
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19
Q

What are cytolytic toxins?

A

Toxins that cause cell lysis

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20
Q

What are Dermonecrotic toxins?

A

Toxins that disrupt skin cells

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21
Q

What are neruotoxins?

A

Toxins that disrupt nerve cells

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22
Q

What is the structure of bacterial exotoxins?

A
  1. They can be single proteins or organised into oligomeric protein structures.
  2. Usually organised into AB structure/function properties.
  3. The A domain is the catalytic domain.
  4. The B domain usually has a receptor binding domain and a translocation domain.
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23
Q

What are some examples of catalytic functions of exotoxins?

A
  1. ribosylation
  2. Glucosylation
  3. proteolysis
  4. Non-covalent modification of host proteins.
  5. modification through direct binding of host proteins
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24
Q

What are the 5 main types of bacterial exotoxins?

A
  1. Single polypeptide toxins
  2. Binary toxins
  3. Oligomeric toxins
  4. Protoxins
  5. Pore-forming toxins
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25
Q

What are binary exotoxins?

A
  1. They consist of 2 independent polypeptide chains
  2. Also called non-associated AB toxins
  3. Eg anthrax toxin
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26
Q

What are oligomeric exotoxins?

A
  1. Multimeric complexes consisting of 2 or more non-covalently linked subunits
  2. ABn toxins
  3. Eg cholera toxins
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27
Q

What are single polypeptide exotoxins?

A
  1. AB toxins
  2. Eg Diphtheria toxin
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28
Q

What are Protoxins?

A
  1. These are secreted in an inactive form.
  2. These can be converted to an active form by proteolytic enzymes
  3. These can be host or bacterial enzymes
  4. Eg lota toxin
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29
Q

What are Pore-forming toxins?

A
  1. Monomeric or bi-component molecules
  2. They bind to specific cells and oligomerise on the surface resulting in a cell membrane pore.
  3. This leads to cell lysis
30
Q

What is cholera toxin?

A
  1. A toxin produced by the gram-negative vibrio cholerae which causes cholera.
  2. Transmitted through the faecal-oral route.
  3. Causes lots of diarrhoea.
  4. Responsible for millions of deaths due to rapid dehydration, acidosis and hypovolemic shock
  5. Treatment with rehydration and nutrients and just letting it run its cause.
31
Q

What is the structure of cholera toxin?

A
  1. It is a classic AB5 toxin.
  2. The A domain is composed of 2 poly peptide chains, A1 and A2.
  3. The B domain is made up of 5 identical polypeptide chains.
32
Q

What does cholera toxin bind to?

A
  1. The B domain specifically binds to receptors on intestinal epithelial cells.
  2. The primary receptor is the GM1 gangliosides.
  3. The secondary receptor is histo-blood group antigens.
  4. Binding causes endocytosis.
32
Q

What happens to cholera toxin when it is internalised and acts in the cell?

A
  1. It is internalised into an endosomal compartment and trafficked to the golgi then the ER.
  2. In the ER, the toxin dissociates and the A domain is exported to the cytosol.
  3. The A domain binds ADP ribosylation factor 6 (ARF6).
  4. ARF6-CTX-A activates adenylyl cyclase
  5. Adenylyl cyclase catalyses the conversion of ATP to cyclic AMP and increasing the intracellular cAMP conc.
  6. This activates protein kinase A.
  7. PKA phosphorylates the CFTR chloride channel protein.
  8. This results in the release of electrolytes and water into the intestinal lumen, causing diarrhoea.
33
Q

How does the action of cholera toxin help the bacteria?

A
  1. The diarrhoea increases the transmission of disease.
  2. It gets the bacteria out of the host and into the environment and to another host.
34
Q

What is the secondary role of cholera toxin?

A
  1. Several gut bacteria mimic host proteins like GM1.
  2. This makes them less likely to be recognised by the immune system.
  3. But it also means that cholera can bind to them.
  4. Cholera uses this to eliminate competition by inhibiting growth of the colonisers.
35
Q

What is the background of botulinum toxin?

A
  1. A toxin produced by the gram-positive, anaerobic, spore-forming bacteria. Clostridium botulinum.
  2. It is very prevalent in soil and marine sediments worldwide.
  3. Botulism can occur as a result of food (canned, homemade, preserved or fermented) or wound contamination.
  4. Eradication of spores is central to preventing infection. This is done by high temps or pressures.
36
Q

What is botulinum toxin?

A
  1. A binary AB neurotoxin.
  2. The N terminus is a zinc dependent metalloprotease.
  3. This is linked to the C-terminal B fragment by a disulphide bond.
37
Q

How does the neurotransmitter acetylcholine (ACh) normally function?

A
  1. ACh is released from a synaptic vesicle at the neuromuscular junction via the assembly of the SNARE complex.
  2. ACh vesicle fuses with the nerve cell membrane and is released into the synaptic cleft and binds to receptors on muscle cells.
38
Q

What is acetylcholine?

A

The primary neurotransmitter of the parasympathetic nervous system that enables smooth muscle contraction.

39
Q

What is the SNARE complex?

A
  1. Made up of synaptobrevin, SNAP-25 and syntaxin.
  2. It allows fusion of the vesicle to the membrane to release ACh.
40
Q

How does ACh function when botulinum toxin (BoNT) is present?

A
  1. BoNT binds to the receptor and is endocytosed.
  2. The BoNT light chain cleaves SNARE proteins to prevent assembly.
  3. There are a variety of different BoNT toxins with different light chains that cleave SNARE proteins at different sites.
  4. This blocks the release of ACh and causes flaccid paralysis.
41
Q

What receptors does botulinum neurotoxin bind to?

A
  1. Polysialoganglioside.
  2. the synaptic vesicle proteins synaptotagamin and synaptic glycoprotein.
42
Q

How does botulinum neurotoxin help the bacteria?

A

Playing the long game
1. It is not a human specific pathogen so can cause animal death.
2. When the animal dies, the spores enter the soil along with nutrients.
3. The bacterial spores germinate and grow.
4. The spores can potentially promote plant growth and lead to onwards transmission.
5. It is also thought that BoNT could have some specific soil activity with an undiscovered selected advantage.

43
Q

What are leukotoxins?

A
  1. Attacks leukocytes/WBC
  2. They are produced by several genera of bacteria but mostly staphylococcus.
  3. Major problem with antibiotic resistance.
  4. Has a massive health and economic burden.
  5. Causes a wide range of infections like skin infections or pulmonary disease
  6. S. aureus has a large range of virulence factors which are important for colonisation and disease progression
44
Q

What is the other name of leukotoxins?

A

Leukocidins

45
Q

What are the 2 main types of leukotoxins?

A
  1. Receptor binding
  2. Receptor independent.
46
Q

What are receptor binding luekotoxins?

A
  1. The toxin binds to a specific receptor and causes formation of a pore.
  2. There are usually 1 or 2 components that oligomerise.
  3. This pore formation causes cell lysis.
47
Q

What are receptor-independent leukotoxins?

A
  1. They interact with the lipid membrane and cause disintegration of the membrane.
  2. They then form a pore.
  3. They target lots of different cell types.
  4. They are often short alpha-helical peptides that are amphipathic.
48
Q

What does the leukotoxin, α-haemolysin do?

A
  1. A receptor binding toxin
  2. One of the most characterised bacterial toxins
  3. The monomer binds ADAM10 on RBC.
  4. Then, the monomers oligomerise to form a pore that is inserted into the membrane.
49
Q

What are bicomponent leukocidins?

A
  1. They have 2 different subunits.
  2. The S-subunit binds to the receptor first.
  3. The F-subunits binds later and dimerises.
  4. There is then oligomerisation to form the pore and then insert it into the membrane.
50
Q

Why does S. aureus use lots of leukotoxins?

A
  1. Neutrophils are very important for the S.aureus defence.
  2. This is shown in people with neutrophil deficiencies and recurring staph infections.
  3. So S.aureus attacks the hosts main defence.
51
Q

What receptor does α-haemolysin bind?

A

ADAM10 on RBC

52
Q

What receptor does LukE D bind?

A

CCR5 on T cells, macrophages and dendritic cells.

53
Q

What receptor does PVL bind?

A

C5aR on PMN and monocytes

54
Q

What receptor does LukAB bind?

A

CD11B on PMN, monocytes, macrophages and dendritic cells.

55
Q

What is the common theme with the receptors that staph toxins target?

A

They are all receptors that are highly expressed on immune cells.

56
Q

Do leukotoxins affect all species the same?

A
  1. No
  2. Different species have different susceptibility to the toxins.
  3. This is based on the levels of the target receptor expression.
57
Q

Why is considering the variation in species susceptibility to leukotoxins important?

A
  1. Rabbit cells have higher ADAM10 expression so are more susceptible to a-haemolysin.
  2. Mice cells don’t really express C5aR so they are not susceptible to PVL.
  3. This means the receptor expression needs to be considered when selecting animal models to select the effect of toxins.
58
Q

What are phenol-soluble modulins?

A
  1. Receptor independent toxins
  2. They work in synergy with ß-toxin.
  3. ß-toxin breaks down the sphingomyelin in the membrane to improve the interactions of the phenol-soluble modulins.
  4. The phenol-soluble modulins then cause membrane disruption and form pores to cause cell lysis.
59
Q

How does the action of leukotoxins aid the bacteria?

A
  1. Nutrient acquisition
  2. Target and kill immune cells.
  3. Transmission via pus
60
Q

What are the other roles toxins can do?

A
  1. S.aureus PSMs are important for phagosomal escape and replication in the cytosol.
  2. PSMs can also inhibit the growth of commensal microbes to allow staph to dominate especially in the nose.
  3. Lots of staph toxins can also modulate biofilms with nutrient uptake or waste escape.
61
Q

What is the enterotoxin Shiga toxin?

A
  1. It is an AB5 toxin.
  2. It is produced by E. coli (O157:H7)
  3. It is an enterohaemorrhagic E.coli that causes lots of disease in humans
  4. A prophage in the genome encodes the Shiga toxin.
  5. It has a key role in disease progression.
  6. It is transmitted to humans from cow via contaminated food, water, animals, infected people and contaminated surfaces.
62
Q

What is the structure of Shiga toxin?

A
  1. AB5 toxin
  2. Catalytic A subunit covalently attached to a pentamer of identical B subunits.
63
Q

When is shiga toxin expressed?

A
  1. It is expressed during the lytic cycle of the phage in the genome.
  2. It is secreted by phage mediated bacterial lysis
64
Q

What environment is Shiga toxin regulated by?

A
  1. Iron environment
  2. Its action is restricted at high iron concentrations
  3. So it is mostly produced in low iron distal small intestine and colon.
65
Q

What receptor does Shiga toxin bind to?

A
  1. Globotriaocylceramide (Gb3)
  2. This is a cell membrane glycolipid
  3. It initiates endocytosis and internalisation.
66
Q

What happens when Shiga toxin is internalised into the host cell?

A
  1. It is localised to the early and recycling endosome.
  2. The retrograde trafficking machinery shuttles the toxin from the endosome to the Golgi and then the ER.
  3. This trafficking requires clathrin and retromer to make the vesicles.
  4. Then Retro-translocation translocates the A subunit to the cytosol.
  5. Furin cleaves the C terminal A subunit but is remains linked by disulphide bonds.
  6. The ER lumen reduces the disulphide bonds and the A domain is released.
67
Q

What is the Shiga toxin mechanism of action?

A
  1. The A subunit is an N-glycosidase.
  2. When released the A subunit is active.
  3. It hydrolyses the N-glycosidic bond of an adenosine at position 4324 in the 28S rRNA gene.
  4. This targets the 28S rRNA of the eukaryotic ribosome.
  5. This inhibits aminoacyl tRNA binding to the A site of the 60S ribosomal subunit which prevents peptide elongation, protein synthesis and causes cell death.
68
Q

What are some alternative roles of Shiga toxin?

A
  1. Toxins evolved to allow bacteria to compete or establish a niche.
  2. Shiga can provide protection from predation and parasite.
  3. There is evidence that Shiga toxin is important for intestinal colonisation.
69
Q

What evidence is there that Shiga toxin can provide protection from protozoa?

A
  1. Using 2 strains of E.coli 1 with Shiga and 1 without in a protozoa rich environment.
  2. This Shiga+ strain survives much better.
  3. When adding GFP you can see Shiga+ strain survive and see Shiga- strains being digested.

Frontiers in infectious diseases (4 decks)

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