KOCH'S POSTULATES (1890)
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- The microorganism must be regularly isolated from cases of disease.
- It must be grown in pure culture in vitro.
- When a pure culture is inoculated into a susceptible animal species,
the typical disease must result.
- The microorganism must be isolated from the animal.
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KOCH'S POSTULATES - INADEQUATE?
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1 Ancient epidemic diseases.
2. First postulate - implication that disease is independent of the
host.
3. Second postulate - not all infectious agents can be cultured.
- Treponema pallidum
- Mycobacterium leprae
4. Second and fourth postulate - implication:
- (a) uniform virulence
- (b) cause and single disease.
- (i) Single species - different strains variable virulence and
different diseases.
- (ii) Same symptoms - different species and genus.
- (iii) Polymicrobic infections.
- (iv) Cultivation on laboratory media - loss of virulence.
- (v) Some diseases - unique to humans. Therefore, cannot be tested.
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Why study how bacteria cause disease?
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- Pre 1940s Infectious disease serious problem world- wide and control
success was from:-
- (a) higher standard of living
- (b) public works investment e.g. water, sewage.
- 1945-1990 Infectious disease in developed countries greatly reduced - antibiotics.
- 1990 onward Infectious disease an increasing problem:-
- (a) Misuse of antibiotics in medicine
- (b) Misuse of antibiotics in agriculture
- (c) Change in society - drug abuse - travel
Multiresistant Mycobacterium tuberculosis and Staphylococcus
aureus
- Requirement for new anti-infective agents.
Virulence factors as targets
- Drug development in other areas of medicine.
- a) ACE, angiotensin converting enzyme (high blood pressure).
Captopril - Brazilian viper venom mechanism.
- b) Selective blocking of calcium gated potassium channels in T-lymphocytes
by the venom of scorpions. Possible immuno suppressive drug:
- - autoimmune diseases
- - graft rejection
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KOCH'S POSTULATES FOR GENES
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Traits that give the bacterium its pathogenic potential
Gene = gene product
- 1. Gene present in bacterium causing the disease
- 2. Gene absent in avirulent bacterium
- 3. If present in an organism which does not cause the disease
- - mutated
- - not expressed
- 4. Disrupt gene avirulent
- 5 Introduction of the gene
- avirulent - virulent
- N.B. More than one gene may be required for virulence
- 6 Gene expressed during infection
- 7 Antibodies to the gene product or cell mediated response is protective
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PATHOGENS
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Intracellular |
Extracellular |
| Host attack |
Protected |
Not protected
antibody
complement |
| Cell type |
Immune cells - esp. macrophages
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| Treatment |
Difficult |
Easier |
| Tissue destruction |
High |
Lower |
| Dissemination |
Low |
High |
| Spread within host
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Low |
Higher |
| Growth |
Low |
High |
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MAJOR PHASES IN INFECTION
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Enter body
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Attach to structures
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colonisation factors,
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adhesins
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pili
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binding proteins
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Enter host cell
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Extracellular growth
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Phagocytosis
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Macrophages
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Induced
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Invasins
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Multiply |
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Shed
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Dependent on the host state and the speed to mount a specific response.
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Host Defences
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- Antimicrobial molecules
- Lysosyme - skin, eye
- Defensins - skin, gut
- Wash-out
- skin
- Oropharynx
- Respiratory tract
- Alimentary canal
- Eye
- Urinary genital tract
- Normal microflora
- Skin
- Respiratory tract
- Alimentary canal
- Female genital tract
- Immune systems
- All sites
- Mucosal surfaces
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EVASION STRATEGIES
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A text version of this table
is provided for browsers that cannot handle tables.
| Defence |
Microbial strategy |
Mechanism |
Example |
| Wash-out |
Bind to cell |
Adhesins |
Neisseria |
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Inhibit ciliary activity |
Ciliotoxic/ciliostatic molecule |
Bordetella Streptococcus |
Ingestion and
killing by
phagocyte |
Disrupt chemotaxis
cytotoxic |
Leucocidins |
Staphylococcus |
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Inhibit phagocytosis |
Capsule |
Streptococcus |
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Inhibit lysosomal
fusion
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Inhibitory molecule |
Mycobacterium |
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Multiply |
Unknown |
Listeria |
Restrict Fe -
Lactoferrin
Transferrin |
Compete |
Siderophore |
Mycobacterium
Escherichia |
| Activate complement
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Interfere with
alternative pathway |
Fully sialylated surface |
Neisseria |
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Inactivate |
Elastase |
Pseudomonas |
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Antigen projects
beyond surface |
Activation occurs
at the wrong site |
Gram-negatives |
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Interfere with
complement-
mediated
phagocytosis
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C3b receptor competition,
microbe and phagocyte |
Streptococcus |
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Barrier systems
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| Host cell membrane |
Taken up by phagocyte and resist killing |
Inhibitory molecule |
Mycobacterium |
| Production of antibody |
Degrade antibody |
IgA protease |
Streptococcus |
| Antimicrobial cell-mediated response |
Activate T cells non-specifically and productively |
Superantigen |
Staphylococcus |
| Antimicrobial immune response |
Vary presenting microbial antigen |
Switch on production of different antigens |
Borrelia |
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Genetic recombination |
Streptococcus |
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DIRECT MECHANISMS
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Exotoxins and exoenzymes.
Gram-positive.
Staphylococcus aureus 30% weight
- 1 Specific actions - Toxins
e.g. tetanospasmin
- 2. Less specific actions.
- Proteases - protein, polypeptides
- Hyaluronate lyase - hyaluronic acid
- Lipases - triglycerides
- DNase-DNA
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SPREAD
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Many A fragments ribosylate a target protein.
One molecule of A can kill one cell
NAD + Target
leads to
Nicotinamide + ADP - ribosyl protein.
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Toxin
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Receptor
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Endocytic
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Target
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Effect
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Diptheria
phage
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Heparin binding epidermal growth factor
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+
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Elongation factor 2
Ribosylation
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Inhibition of protein synthesis
- mycocardial cells especially susceptible
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Botulinum
phage plasmid
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Peripheral nerves glycoprotein
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-
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Synaptobrevins
(synaptic vesicles) Zinc-dependent endoeptidase
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Inhibits release of acetyl choline.
No stimulation - flaccid paralysis
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Tetanus
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Central nerves
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-
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Synaptobrevins
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Inhibits release of gamma-amino butyrate.
No inhibition of action - spastic paralysis
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Cholera
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GMI gangliosides
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Pore?
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G-proteins ribosylation
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C-AMP rises.
NaCl lost water from blood.
Diarrhoea - 40L per day
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Pertussis
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Lactosyl
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?
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G-proteins ribosylation
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C-AMP as in cholera.
Mucous secretion
?cough
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No functional differences in toxin structure.
Membrane active
Pore-forming
Staphylococcus aureus alpha-toxin
Listeria monocytogenes Listeriolysin 0
Pore forming ability in cytoplasmic and vesicle membranes
Enzymatic
Clostridium perfringens alpha-toxin, a phospholipase
Superantigens
Staphylococcus aureus Enterotoxins: TSST - 1 |
MEDICAL USE OF TOXINS
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- 1. Reagents - understand a normal mechanism
- 2. Therapy
- (a) Present example
- Botulinum toxin
- Dystorias - painful spasms
- face and neck
- local injections.
- (b) Future
Diphtheria toxin - genetically engineered.
A component - new binding molecule for cancer cells.
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Link to list of topics
Page edited April 2006
Microbiology Teaching Page
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© Prof. Keith Holland 2003
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