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Microbiology And Immunology > Bacterial pathogens and disease I (exotoxins) > Flashcards

Bacterial pathogens and disease I (exotoxins) Flashcards

1
Q

What is a pathogen?

A

A microorganism capable of causing disease

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2
Q

What is pathogenecity?

A
  • The ability of an infectious agent to cause disease
  • The set of mechanisms that causes disease
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3
Q

What is virulence?

A
  • The quantitative ability of an agent to cause disease
  • The severity or harmfulness of diseases causes
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4
Q

What is toxigenecity?

A
  • The ability of a microorganism to produce a toxin that contributes to the development of disease.
  • Toxins don’t lead to disease - they only contribute to the development of disease
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5
Q

State the 4 main mechanisms required for virulence?

A
  1. Adherence factors
    a. Proteins which allow for bacteria to attach to surface
  2. Biofilms
    a. Elements which allow bacteria to produce 3D communities
    B. Allows for hibernation of bacteria + increased protection from antibiotics and host defences
  3. Invasion of host cells + tissues
  4. Toxins - endotoxins and exotoxins
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6
Q

What are exotoxins?

A
  • Heterogeneous 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
  • Remember toxins don’t actually cause the disease - they contribute to the development
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7
Q

What selective advantages do exotoxins give to bacteria?

A
  • Cause disease? - may help transmission of disease via carriage, however in severe disease host may be a literal and evolutionary dead end
  • My thinking here is that bacteria needs to continue replicating - causing severe effects is likely to be fatal, so bacteria will not be able to continue to proliferate without a host if it dies
  • However with many toxins the disease causing activity may be not be the primary function.
  • Other activities: Evade immune response, Enable biofilm formation, Enable attachment to host cells, Escape from phagosomes
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8
Q

What are the 3 main evolutionary advantages that endotoxins give bacteria?

A
  • Colonisation
  • Niche establishment
  • Carriage - Transmission of disease
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9
Q

Why does Staphylococcus aurues have exotoxins?

A
  • Can release
    1. Haemolytic toxins
  • Causes cells to lyse by forming pores
  • Important cause of features of S.aureus disease
  • e.g. a,.,, toxins, Panton Valentine Leukocidin (PVL), LukAB, LuKED, LukM
  1. Phenol soluble modulins (PSM)
    - Aggregate the lipid bilayer of host cells - lysis

Majority of S. aureus in humans is asymptomatic carriage in the nose

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10
Q

In C.difficile, what can exotoxins be encoded by?

A

Can be encoded by chromosomal genes Shia toxin in Shigella dysenteriae, TodA & TedB in C. difficile

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11
Q

What are most toxins encoded by and given examples?

A
  • Many toxins coded by extrachromosomal genes
  • Any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell.
  • Examples: Plasmids - Bacillus anthracis toxin, tetanus toxin
  • Lysogenic bacteriophage - e.g. streptococcal pyrogenic exotoxins in
    Scarlet Fever, Diphtheria toxin.
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12
Q

State how exotoxins are classified?

A
  • Classification is based upon the toxins activity - due to very diverse group of proteins with lots of ways to classify
    1. Membrane Acting Toxins - Type I
    2. Membrane Damaging Toxins - Type II
    3. Intracellular Toxins - Type III
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13
Q

What are the problems behind the classification of exotoxins?

A
  • Many toxins may have more than one type activity.
  • As mechanisms better understood this classification tends to break down.
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14
Q

Describe the mechanism of action behind type I exotoxins?

A
  • Type I - Membrane acting
  • Act: They act from without the cell
  • Interfere: Interfere with host cell signaling by inappropriate activation of host cell receptors.
  • Target (upregulation) of target receptors:
    • Guanylyl cyclase - ½ intracellular cGMP
    • Adenyl cyclase -> Increase intracellular cAMP
    • Rho proteins
    • Ras proteins
  • Typically leads to increase in conc. of ions outside the cell?
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15
Q

What is the main effect of Type I - E. coli stable heat toxin?

A
  • Diarrhoea due to increased conc. of ions (e.g. CI-, HCO3-, Na+) outside the cell due to inappropriate activation of cGMP
  • VD
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16
Q

State how Type II endotoxins work and give examples of the different types of mechanisms and examples of these?

A
  • Type II - Membrane damaging
    Primary action: Cause damage to the host cell membrane.
    Same thing, but different ways of classifying mechanisms:
    1. Insert channels into host cell membrane / Receptor - mediated
    a. disrupts the transport of ions - disrupting potential - cell lysis
    Examples
    1. B sheet toxins e.g. S.aureus a - toxin, toxin, PVL
    2. a helix toxins - e.g. diphtheria toxin
    2. Enzymatical damage/ Receptor independent
    a. Attach to membrane - Membrane disintegration - formation of short-lived pores
    b. e.g. S. aureus - haemolysin, PSM
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17
Q

Describe the structure of type Ill exotoxins and why it has this structure?

A
  • Intracellular toxins - type III
    • Active within the cell - must gain access to the cell
    • Usually 2 components - AB Toxins
    • Receptor binding and translocation function - B
    • Allows for toxin to enter into the cell
    • Toxigenic (enzymatic) - A
    • Messes up metabolic pathways of the cell
    • May be single or multiple B units e.g. Cholera toxin AB5
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18
Q

Name two other types of type Ill endotoxins and their method of action with an example for each one?

A
  • 1). Type III secretion + toxin injection
  • Protein structure has a hypodermic needle structure, which injects exotoxins as effector proteins into cells
  • Example : YopE in Yersinina species
  • 2). Type IV secretion and toxin injection
  • Protein complex which pumps toxins
  • E.g. CagA in Helicobacter pylori
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19
Q

Examples of of component A of Type III (ANKI) for next 5 slides
What bacteria and toxin is ADP-ribosyl transferases found in?

A

Exotoxin A of Pseudomonas aeruginosa, pertussis toxin.

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20
Q

What bacteria and toxin is Glucosyltransfereases found in?

A

TedA and TedB of Clostridium difficile

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21
Q

What bacteria and toxin is Deamidase found in?

A

Dermonecrotic toxin of Bordetella pertussis.

22
Q

What bacteria and toxin is Protease found in?

A

Clostridial neurotoxins: botulism & tetanus

23
Q

What bacteria and toxin is adenylcyclase found in?

A

EF (Edema factor) toxin of Bacillus anthracis

24
Q

How exotoxins interact with the immune system
How can exotoxins dysregulate immune? (PART 1)

A
  • Inducing an inflammatory cytokine release - immune system driven into mania and overproduction of cytokines (cytokine storm) leads to an immunopathology (disease associated with immune response)/ toxic shock
  • E.g of these cytokines: IL1, IL1beta, TF, IL6, interferon, IL18
  • These occurs via two main mechanisms: Superantigens and inflammatory cytokines
25
Q

How can exotoxins dysregulate immune? (PART 2)

A
  • Superantigens (exotoxin)
    1. Non-specific bridging of MHC class II (of macrophage) and T-cell receptor leading to cytokine production without presence of antigen -> Activation of large number of T cells -> Producing IF cytokines
    2. Normally occurs to response of specific antigen as only T cells recognises that antigen is activated
    3. E.g. straphylococcal exfloiative toxin A, toxic shock syndrome toxin 1 (TSST1)
26
Q

How can exotoxins dysregulate immune? (PART 3)

A
  1. Activation of different inflammasome leading to release of IL1 beta and IL18 e.g. s.aureus toxin A, PVL
  2. Inflammasome is innate immune system receptors/sensors which detect damage or infection -> production of cytokines when activate
27
Q

What are toxoids and what can be they used for giving examples?

A
  • Toxins can be inactivated using formaldehyde or glutaraldehyde -> toxoids
  • Toxoids are inactive proteins but still highly immunogenic - form the basis for vaccines.
  • Examples: Tetanus Vaccine, Diphtheria, Pertussis (acellular).
28
Q

How can treatment of toxin mediated disease occur and state them for diptheria antitoxin, tetanus and botulism?

A
  • Treatment of toxin mediated disease can be affected by administering preformed antibodies to the toxin - these will target the toxin for degradation
  • Diphtheria antitoxin - horse antibodies.
  • Tetanus - pooled human immunoglobulin. Specific or normal.
  • Botulism - horse antibodies
29
Q

What can be used for experimental and research for toxin mediateddiseases?

A

Monoclonal antibodies

30
Q

C.difficle features
State features of the microbiology of clostridium difficile?

A
  • Gram-positive bacillus
  • Anaerobic
  • Spore-forming.
  • Toxin-producing.
  • Can be carried asymptomatically in the gut.
  • Produces 3 toxins.
31
Q

Describe the epidemology with risk factors of C.difficle?

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.
  • Risk factors - antibiotic use, age, antacids & prolonged hospital stay.
32
Q

Why is antibiotics a risk factor for C.difficle?

A
  • Thought to act by disrupting the microbial ecosystem within the gut.
  • Antibiotics provide a competitive advantage to spore forming anaerobes over non spore forming anaerobes.
  • Allows C. difficile colonisation and growth.
  • All antibiotics have potential for causing disease.
33
Q

State 3 examples of the worser antibiotics?

A
  • 2nd and 3rd generation cephalosporins
  • Quinolones
  • Clindamycin?
34
Q

State 3 examples of antibiotics which are less likely to be a risk factor?

A

Aminoglycosides
- Trimethoprim
- vancomycin

35
Q

State the 3 different toxins produced by C.difficile which the gene coded for?

A
  • Cytotoxin A: TedA is coded by TedA gene
  • Cytotoxin B: TedB is coded by TedB gene
  • Binary toxin: C.diff transferase (CDT) - minor role in disease
36
Q

What are Ted A and Ted B?

A
  • A component of toxins are glycosylating enzymes
  • Glycosidases catalyze the hydrolysis of glycosidic bonds to remove sugars from proteins
37
Q

Describe the general structure of TeA and TedB?

A

VD

38
Q

Describe the mechanism by which C.difficle toxin works? (PART 1)

A
  1. The toxins enter cells via receptor mediated endocytosis (toxins bind to specific host cell receptor) and are then internalised in endosome
  2. The endosome is then acidified followed by the release of the active component of the toxin and a pore is formed in the endosome
  3. The GTD is released into the cytoplasm that inactivates the Rho
    GTPase via glucosylation (GTD binds to ho) and causes other downstream cytotoxic effects.
39
Q

Describe the mechanism by which C.difficle toxin works? (PART 2)

A
  1. The effects of the cytotoxicity and cytopathic activity is:
    - a. Cytopathic (structural changes in host cell) - cytoskeleton breakdown, loss of cell to cell contacts and increased epithelial permeability
    - b. Cytotoxicity - Activation of inflammasome, Increase in ROS levels and induction of programmed cell death
40
Q

State the impacts of the cytopathic and cytoxin effects of C.difficle? (3)

A
  • Patchy necrosis with neutrophil infiltration
  • Epithelial ulcers
  • Pseudomembranes - leucocytes, fibrin, mucous, cell debris.
  • Pseudomembrane - a layer of exudate resembling a membrane, formed on the surface of the skin or of a mucous membrane, especially the conjunctiva.
41
Q

State the progression of symptoms of C.difficle?

A
  • Asymptomatic -> watery diarrhoea -> dysentry (infection of intestines) -> pseudomembranous colitis -> toxic megacolon and peritonitis
42
Q

State methods used to aid in the diagnosis of C.difficle?

A
  • Clinical signs and symptoms
  • Raised white cell count in blood.
  • Detection of organisms and toxins in stool
  • 2 phase test: 1. Glutamate dehydrogenase - detects if C. difficile organism present. 2. Toxin enzyme linked immunosorbent assav ELISA) for TcdA and TcdB toxins.
  • Detection of todA and ted genes - PCR
  • Important gene as organism may be in host, but gene is not expressed
  • Colonoscopy - pseudomembranous colitis
43
Q

State the treatments for C.difficile?

A
  • Treatment dependent on severity and presence of surgical complications
  • Ideally removal of offending antibiotic - not always possible
  • Antibiotics fidaxomicin or metronidazole or vancomvcin - these work against the bacteria
  • Surgery - partial, total colectomy
  • Recurrent - faecal transplant: Recolonises the gut to expel C.difficle
44
Q

What is VTEC/STEC, what does it produce and how is it usually identified?

A
  • Verocytotoxin Escherichia coli disease (VTEC), or Shiga-toxin (Stx) producing E. coli (STEC) can cause disease mild to life threatening disease.
  • St carried by some E. coli - most commonly 0157:H7
  • Identified in comparison to normal E.coli usually by growth on sorbitol MacConkey agar (SMac) - VTEC does not ferment sorbitol and hence is clear.
  • Other less common types not identified using SMac.
45
Q

Describe the epidemology and transmission of VTEC?

A

E. coli 0157:7 naturally colonizes the gastrointestinal tracts of cattle who are generally asymptomatic.
- Transmission:
- 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 camp grounds.
- Very low infectious dose required to cause outbreak

46
Q

Describe features of the pathogenesis toxin of STEC/VTEC stating examples of different types of toxins?

A
  • Toxin - Shiga like toxin (SLT) = shigatoxin (Stx) = verocytotoxin (VTEC)
  • Stx, Stx1, Stx1a, 1c, 1d St×2a, 2c, 2d - variations in a.a. sequence
  • Gene carried on lysogenic virus - method by which a virus can replicate its DNA using a host cell
  • Type III exotoxin - AB5
  • Enzymatic component A = N-Glycosidase
  • Bound to 5 B subunits
47
Q

Describe the mechanism of STEC/VTEC toxin pathogenesis? (PART 1)

A
  • Bind to receptor globotriaosylceramide Gb3 or globotetraosv|ceramide (Gb4) on host cell membrane
  • Bound toxin internalised by receptor mediated endoctosis.
  • Carried by retrograde trafficking via the Golgi apparatus to the endoplasmic reticulum. •
  • The A subunit is cleaved off by membrane bound proteases
48
Q

Describe the mechanism of STEC/VTEC toxin pathogenesis? (PART 2)

A
  • Once in the cytoplasm A1 and A2 disassociate
  • A1 binds to 28S RNA subunit - blocks protein synthesis.
  • The B domain gives this toxin the ability to bind to endothelial as well as epithelial cells. It will then enter the body via the guy
49
Q

Describe the pathogenesis of STEC/VTEC?

A
  • STEC closely adheres to the epithelial cells of the gut mucosa.
  • The route by which St is transported from the intestine to the kidney and other tissues is debated, possibly polymorphonuclear neutrophils (PMNs)
  • Bind to glomerular endothelial cells of kidney, cardiovascular and central nervous system. •
  • Very high levels of Gb3 (target receptor of Stx) in kidney so kidneys most affected.
  • Thought that St favours inflammation resulting in microvascular thrombosis and inhibition of fibrinolysis.
50
Q

State the common findinds in STEC disease?

A
  • Can be severe and life threatening
  • Children < 5 years are at greatest risk
  • Abdominal cramps, watery or bloody diarrhoea - may not be present
  • Causes Haemolytic uraemic syndrome which can lead to : Anaemia, Renal Failure, Thrombocytopenia
  • Less common are neurological symptoms: lethargy, severe headache, convulsions, encephalopathy
51
Q

State the tests used for the diagnosis of STEC?

A
  • Clinical signs and symptoms
  • Haematological and biochemical evidence.
  • Stool culture - Growth on SMac
  • PCR for St genes
52
Q

What is used for the treatment of STEC?

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

Microbiology And Immunology (32 decks)

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