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SEM 4: Medical Microbiology > Exotoxins > Flashcards

Exotoxins Flashcards

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Biology 101 flashcards USMLE® Step 1 flashcards
1
Q

Define pathogen

A

Microorganism capable of causing disease

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2
Q

Define pathogenicity

A

The ability of an infectious agent to cause disease.

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3
Q

Define virulence

A

The quantitative ability of an agent to cause disease.

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4
Q

Define toxigenicity

A

The ability of a microorganism to produce toxin that contributes to the development of diseases.

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5
Q

What are the virulence mechanisms?

A
  • Adherence factors
  • Biofilms
  • Invasion of Host Cells and Tissues
  • Toxins - endotoxins and exotoxins
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6
Q

Define an exotoxin

A
  • Heterogenous group of proteins produced and secreted by living bacterial cells.
  • Produced by both gram negative and gram positive bacteria
  • Cause disease symptoms in host during disease
  • Act via a variety of diverse mechanisms
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7
Q

Selective advantages do exotoxins give to the bacteria

A
  • Exotoxins cause disease that helps with the transmission of the disease.
  • Only in severe disease can they cause death meaning the bacteria will not replicate and be a dead end.
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8
Q

What are the other activities that exotoxins can do?

A
  • Evade immune response of host
  • Enable biofilm formation
  • Enable attachment to host cells
  • Escape from phagosomes
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9
Q

What is a biofilm?

A

A biofilm is a densely packed community of bacteria that grows on an inert surface.

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10
Q

Importance of action of exotoxins

A

They allow for colonisation, niche establishment and carriage which means they are an evolutionary advantage.

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11
Q

Example of a gram-positive bacterium

A

Staphylococcus aureus

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12
Q

Toxins produced by staphylococcus aureus

A

Haemolytic toxins and Phenol soluble modulins (PSM)q

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13
Q

Haemolytic toxins and staphylococcus aureus

A

The haemolytic toxins cause pores in the cell membrane of host cells by causing the cell to lysis.
This is an important feature of S. aureus disease.

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14
Q

Phenol Soluble Modulins

A

They cause the lipid bilayer of host cells to break down through aggregation - lysis.

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15
Q

Where does the majority of S. aureus reside?

A

In the nose of humans and doesn’t cause disease

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16
Q

Functions of the toxins from staphylococcus aureus in the nose

A
  1. PSMs and alpha toxins prevent the formation of the phagolysosome formation by preventing fusion of the lysosome
  2. PSMs kill other cohabiting bacteria so that s. aureus has an advantage by reducing competition
  3. PSMs have surfactant properties allowing s. aureus to slide across surfaces such as an agar plate without having flagella and pili.
  4. Alpha toxins enables the bacteria to attach to a surface and grow. It then forms a secondary structure beta toxins and PSMs which allow for biofilm formation and detachment so that the bacteria can go and disperse to new sites of infection.
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17
Q

Genetics of Exotoxins

A
  • Can be encoded by chromosomal genes e.g. Shiga toxin in Shingella dysenteriae
  • Can be encoded by extrachromosomal genes
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18
Q

Examples of plasmid extrachromosomal genes

A

Bacillus anthracis toxin

Tetanus toxin

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19
Q

Examples of lysogenic bacteriophage extrachromsomal genes

A

Streptococcal pyrogenic exotoxins in Scarlet fever

Diphtheria toxin

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20
Q

Classification of toxins

A

Type 1 - Membrane acting toxins
Type 2 - Membrane damaging toxins
Type 3 - Intracellular Toxins

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21
Q

Problems with classification of toxins

A
  • Many toxins have more than one activity

- As mechanisms better understood this classifcation tends to break down.

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22
Q

Membrane acting toxin - Type 1

A

Act from outside the cell
Interfere with host signalling by inappropriate activation of host cell receptors on membrane
Target receptors including guanylyl cyclase (increase intracellular cGMP), adenyl cyclase (increase intracellular cAMP), Rho proteins and Ras proteins.

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23
Q

Example of a Type 1 membrane acting toxin

A

E. coli heat stable toxin Sta.

  1. Sta is the heat stable toxin that binds to its receptor (GC-C) on the cell membrane.
  2. When the heat stable toxin binds to the ECD (extracellular domain) of the GC-C receptor it increases the production of cGMP.
  3. This will act on the cystic fibrosis transmembrane conductance regulator (CFTR) which normally pumps out chloride and bicarbonate ions out of the cell.
  4. This secretion of electrolytes into the intestinal lumen is followed by water release which is the physiological basis of secretory diarrhoea induced by overactivation of GC-C by STa and CFTR chloride.
  5. A second target for cGMP is the Na+/H+ exchanger in the intestinal epithelial cells. PKA inhibits the reabsorption of sodium by NHE.
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24
Q

What is the GC-C receptor?

A

A key receptor in regulating electrolyte level and the fluidity of the intestinal content.

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25
Q

What is the Cystic Fibrosis Transmembrane Conductance regulator?

A

This is a chloride and bicarbonate ion channel

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26
Q

Membrane damaging toxins - Type II

A
  • Causes damage to the host cell membrane.
    1. It can insert channels into host cell membrane e.g. receptor mediated; b sheet toxins and a helix toxins.
    2. Enzymatic damage e.g. S. aureus B-haemolysin, PSM or receptor independent.
27
Q

Action of membrane damaging toxins

A

Channels are inserted into a membrane which can form pores for example PSM can also break down the cell and form pores.

28
Q

Intracellular toxins - Type 3

A
  • Active within the cell - must gain access to the cell.
  • Usually 2 components, one which allows toxin to enter and one which causes the damage -> AB toxins.
  • > B (Binding) - receptor binding and translocation function
  • > A (Action) - Toxigenic (enzymatic)
  • May be single or multiple B units e.g. Cholera toxin AB5
29
Q

Examples of enzymatic component A

A
  • ADP - ribosyl transferases e.g. Exotoxin A of Pseudomonas aeruginosa. pertussis toxin
  • Glucosyltransferases e.g. TcdA and TcdB of Clostridium difficile - modify ribosomal RNA and inhibits protein synthesis
  • Deamidase e.g. dermonecrotic toxin of Bordetella pertussis
  • Protease e.g. Clostridial neurotoxins: botulism and tetanus - damages the presynaptically vesicles in neurons
  • Adenylcyclase e.g. EF toxin of Bacillus anthracis
30
Q

Other type of type 3 toxin

A

Needle like System - Bacteria have this system which will directly insert the toxin inside the cell without interaction with a specific receptor. An example of this is the YopE in Yersinia species and CagA found in H. pylori.

31
Q

What happens when exotoxins are secreted from bacterial cells?

A

They will induce inflammatory cytokine release such as IL1, IL1beta, TNF, IL 6, d interferon, IL18.

32
Q

How is inflammatory cytokine release carried out?

A

Either directly or through a superantigen.

33
Q

Formation of a superantigen

A
  1. The exotoxins bind to the MHC class II complex of the major professional antigen presenting cells such as macrophages.
  2. They also bind to the receptors on the T cells.
  3. They form a bridge between the APC and the T cell - this is the superantigen.
34
Q

Consequence of superantigen activation

A
  • Leads to excessive production of cytokines including interferon gamma which leads to excessive production of interleukins and more macrophage activation and major T lymphocytes up to 20%.
  • The whole process leads to hyperactivation of the immune system (T lymphocytes) which can lead to shock. e.g. Toxic shock syndrome due to staphylococcal Exfoliative Toxin A.
35
Q

Besides superantigens, how else is inflammatory cytokine release carried out?

A
  1. Via the inflammasome which will detect damage to cells.
  2. This results in activation of the different inflammasome leading to the release of IL1beta and IL18 e.g. S. aureus toxin A, PVL.
36
Q

What are toxoids?

A

Toxins inactivated by using formaldehyde or glutaraldehyde

37
Q

Function of toxoids

A

Although inactive toxins, they are still highly immunogenic and form the basis of vaccines such as tetanus vaccine, diphtheria and pertussis (acellular).

38
Q

How is toxin mediated disease treated?

A

By administering preformed antibodies to the toxin e.g. diphtheria antitoxin -> Horse antibodies

39
Q

Explain diphtheria toxin

A

Injected into horses and antibodies produced are taken and administered to humans.

  • > Tetanus -> Pooled human immunoglobulin - specific or normal.
  • > Botulism -> Horse antibodies
40
Q

Clostridium Difficile

A
  • Gram positive bacillus
  • Anaerobic
  • Spore-forming
  • Toxin-producing
  • Can be carried asymptomatically in the gut
  • Produces 3 toxins
41
Q

Epidemiology of Clostridium Difficile

A
  • Common hospital acquired infection worldwide
  • Spread by ingestion of spores -> remain dormant in environment
  • Coloniser of the human gut up to 5% in adults but doesn’t do any harm
42
Q

Triggers of C. dif disease

A

Antibiotic use
Age
Antacids and prolonged hospital stay

43
Q

How do antibiotics cause C. dif?

A

They disrupt the microbial ecosystem within the gut by:

  1. Antibotics provide a competitive advantage to spore forming anaerobes to non-spore forming anaerobes.
  2. It allows C. difficle colonisation and growth.
44
Q

What are the toxins in C. dif?

A
  • Cytotoxin A -> TcdA coded by the TcdA gene; GTD and CPD enzymes
  • Cytotoxin B -> TcdB coded by the TcdB gene; RBD
  • Binary toxin -> C.diff transferase (CDT) - minor role in disease
45
Q

What type of toxins are the C. dif toxins?

A

Tcd A and Tcd B -> Type III AB toxins.

The A component of toxins are glycosylating enzymes.

46
Q

Action of C.dif toxins

A
  1. B-Toxin will bind to the receptor on cell membrane.
  2. Toxin is phagocytosied and forms an endosome.
  3. This endosome is acidified and allows for the GTD (Cytoxin A) to be released into the host cell cytoplasm.
  4. Bind to Rho GTPases in host which will be inactivated by glycosylation.
  5. This inactive form will have two effects: cytopathic and cytotoxic. Cytopathic is stop the growth of the cytoskeleton. Cytotoxic is the activation of inflammasome, increase in ROS levels and induction of programmed cell death.
47
Q

Symptoms of Cytopathic and Cytotoxic Effects of C. dif Toxin

A
  • Patchy necrosis with neutrophil infiltration
  • Epithelial ulcers
  • Pseudo membranes - leucocytes, fibrin, mucous, cell debris.
48
Q

Diagnosis of C. dif

A
  • > Raised white cell count in blood
    • > Detection of organisms and toxins in stool via ELISA
    • > Detection of tcdA and tcdB genes via PCR
  • > Colonoscopy - pseudomembranous colitis
49
Q

What is the 2 phase C. dif test?

A

1) Glutamate dehydrogenase -> detects if C. dif organism present
2) Toxin enzyme linked immunosorbent assay (ELISA) for TcdA and TcdB toxins

50
Q

Treatment of C.dif

A
  • Treatment depends on severity and presence of surgical complications
  • Ideally removing of offending antibiotic -> however, isn’t always possible.
  • Antibiotics such as fidaxomicin or metronidazole or vancomycin.
  • Surgery - partial, total colectomy.
  • Recurrent C. difficle is treated via faecal transplant. This re-establishes the microbiota.
51
Q

What is verocytotoxin Escherichia Coli (VTEC) (STEC) disease?

A
  • VTEC, Shiga-toxin (Stx) producing E. coli (STEC) can cause disease mild to life threatening disease.
  • Stx carried by some E. coli - most commonly O157:H7.
52
Q

How is Stx identified?

A

Identified usually by growth on sorbitol

  • E. Coli does not ferment sorbitol and hence is clear.
  • Other less common types not identified using SMac.
53
Q

Epidemiology of VTEC

A

E.coli O157:H7 naturally colonises the gastrointestinal tracts of cattle who are generally asymptomatic.

54
Q

Transmission of VTEC

A
  • Predominantly via consumption of contaminated food and water.
  • Person to person, particularly in child day-care facilities, and from animal to person e.g. in petting zoos, dairy farms, or campgrounds.
  • Very low infectious dose
55
Q

Ab5 exotoxin in E.coli

A

Enzymatic component A = N-Glycosidase

Bound to 5B subunits

56
Q

Mechanism of STEC/VTEC disease

A
  1. Toxin will bind to receptors on the surface Gb3 and Gb4.
  2. Bound toxin is internalised by receptor mediated endocytosis.
  3. It is carried by retrograde trafficking via the golgi apparatus to the endoplasmic reticulum.
  4. The A subunit (active component) is cleaved off by membrane bound proteases.
  5. Once in the cytoplasm A1 and A2 dissociate.
  6. A1 binds to the 28S RNA subunit blocking protein synthesis.
57
Q

Pathogenesis of STEC

A
  • It will closely adhere to the epithelial cells of the gut mucosa.
  • The route by which Stx is transported from the intestine to the kidney and other tissue is being debated (possibly polymorphonuclear neutrophils (PMNs).
  • They will bind to glomerular endothelial cells of the kidney, CVS and CNS.
  • There are very high levels of Gb3 in the kidney so the kidney is largely effected.
  • It is thought that Stx favours inflammation resulting in microvascular thrombosis (forms lots of clots) and inhibition of fibrinolysis.
58
Q

Symptoms of STEC disease

A
  • Severe and life threatening
  • Children < 5 years greatest risk
  • Abdominal cramps, watery or bloody diarrhoea -> may not be present
  • Haemolytic uraemic syndrome
59
Q

What is haemolytic uraemic syndrome?

A
  • Anaemia - clots cause RBCs to break down.
  • Cause renal failure
  • Thrombocytopenia (platelets are being consumed due to clot formation)
60
Q

Structure of the VTEC toxin

A

A type 3 AB5 exotoxin with 5 B subunits so can bind to 5 different receptors

61
Q

Neurological symptoms of STEC disease

A
  • Lethargy
  • Severe headache
  • Convulsions
  • Encephalopathy
62
Q

Diagnosis of STEC

A
  • Clinical signs and symptoms
  • Haemtological and biochemical evidence
  • Stool culture -> Growth on SM ac
  • PCR for Stx genes
63
Q

Treatment of STEC

A
  • Supportive including renal dialysis and blood product transfusion
  • Antibiotics have little or no role

SEM 4: Medical Microbiology (15 decks)

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