Damage and Pathophysiology of microbial disease

Question 1

What is visible disease a consequence of?

Answer 1

the consequence of host damage

Question 2

Visible disease is a consequence of host damage. Explain Direct interactions

Answer 2

Production and utilization of offensive virulence factors.

For example Microbial toxins – destroy immune cells and tissues promoting spread, transmission and persistence

Question 3

Visible disease is a consequence of host damage. Explain indirect interactions

Answer 3

Interactions with the host immune responses

For example Inflammation, puss formation, kidney malfunctions due to antibody complexes, endotoxic shock – LPS

Question 4

What do direct and indirect interactions work together to do?

Answer 4

They produce symptoms

Question 5

What are the two categories of toxins?

Answer 5

Exotoxins and Endotoxins

Question 6

(secreted virulence-associated factors) Briefly explain the features of Exotoxins

Answer 6

They are secreted from the cell

Contain both A and B toxins

Site-specific toxins which include those that work on cell membranes

Also includes super antigen toxins

Question 7

Degredative enzymes can also be classed as?

Answer 7

virulence factors - Invasins

For example Collagenase and Hyaluronidase

Question 8

(secreted virulence-associated factors)

Briefly explain the features of Endotoxins

Answer 8

cell wall-associated

Belongs to components of the bacterial or fungal cell wall.

Lipopolysaccharide (LPS) – Lipid A – Gram – ve’s

lipoteichoic acids – Gram positive’s

Zymozan – component of yeast membranes

Exert biological effects by interaction with and over stimulation of the immune system

Question 9

Explain what are Bacterial exotoxins?

Answer 9

Soluble, heat labile secondary protein metabolites produced during growth

Question 10

What are the functions of Bacterial exotoxins

Answer 10

Have functions in the liberation of nutrients from the host and immune avoidance

Question 11

What are the other features of Bacterial exotoxins

Answer 11

Mostly produced in G positives

Have localised and systemic effects

Many carried on plasmids or mobile elements
–bacteriophage

Targets for vaccine design - toxoids

Question 12

What are the two parts of the Protein toxins?

Answer 12

A and B

Question 13

Explain the features and functions of the A part of Protein toxins

Answer 13

A toxic subunit

Acts intracellularly on a specific mechanism

Many different activities

ADP-ribosylation is a common mechanism

Question 14

Explain the features and functions of the B part of Protein toxins

Answer 14

is the protective or binding subunit

Allows entry of A subunit

Allows translocation to the cytosol of the cell

Determines cell tropism

Induces endocytosis or forms pores
»Oligomers – pentamers, heptamers

Question 15

(Protein toxins) How do A and B enter the cell?

Answer 15

Once bound to the Toxin Receptor they under Endocytosis

Question 16

(Protein toxins) Once A and B enter the cell, what happens to the A portion?

Answer 16

The A portion is released into the Cytosol.

The A subunit (portion) will modify a protein designed for protein synthesis

This modification will cause protein synthesis to be stopped, resulting in cell death.

(Refer to slide 8 on Damage and Pathophysiology)

Question 17

What is the Aim of a Diptheria toxin?

Answer 17

The main aim is to interrupt a process of energy manufacture, protein manufacture or the cytoskeletal structure of the cell.

Question 18

Define Site Specific toxins

Answer 18

Work at a particular site in the body

Question 19

Explain Site-specific Neurotoxins

Answer 19

Ingested preformed in food or produced at wound sites

Effect neurones of the gut to cause vomiting

For example:

S. aureus entrotoxin B, B. cereus emetic toxin

Botx – once ingested causes flaccid paralysis

Tetx – produced by an organism in wounds – rigid paralysis

Question 20

Explain Site-specific Enterotoxins

Answer 20

Directly affect fluid secretion or kills cells of the GI tract

For example Cholera toxin - Choleragen

Question 21

Explain Site-specific Cytotoxins

Answer 21

Generally, affect tissue and damage cells directly

Question 22

What do Membrane damaging toxins cause?

Answer 22

Cause lysis by disrupting membrane integrity

Question 23

(Membrane damaging toxins) Explain pore-forming

Answer 23

Kills cells by changing osmotic balance

This includes:

Leukocidins - pneumococci, staph and strep

Hemolysins – Streptolysin S and O
-Cause blood cells to burst depending on O2 availability

Question 24

(Virulence factors) (Membrane damaging toxins) Explain Phospholipases

Answer 24

Remove the charged portion of membrane phospholipids

Including:
C. perfringens alpha toxin

Question 25

(Virulence factors) Explain Super Antigen toxins

Answer 25

-Produced by some bacteria and viruses

For example:
•S. aureus – Toxic shock syndrome toxin and enterotoxin B

-‘Short circuit’ the immune system

Allow non-specific activation of immunity

Switches on cells that produce chemical messengers

-For example:

Cytokines – chemicals that activate or repress immune responses

Can activate >30% of total T cells to produce cytokines

Leads to damage of blood vessels, shock and multi-organ failure

Question 26

(Enzymes used in invasion) What do Invasins promote?

Answer 26

Invasins promote spread

Question 27

(Enzymes used in invasion) What are invasins?

Answer 27

Degredative enzymes used often used in nutrition

•Increase the severity of disease by allowing penetration to deeper tissues

–Kill cells directly, destroy the structure of the tissue, destroy clotts

For example:

Group A Streptococcus pyogenes – Necrotising fasciitis

Extensive destruction of subcutaneous fat and muscle

Production of Hyaluronidase

Streptokinase produced that prevents blood clotting

The net effect is massive and rapid destruction of whole soft tissue areas.

Question 28

(Non-secreted toxic components) Explain the features of Endotoxin

Answer 28

Intrinsic factor found only in G – ve bacteria

•Forms a large component of the outer membrane
For example:
–Lipopolysaccahride - LPS

•Contains Lipid A which anchors the LPS into the outer menbrane–Lipid A is the toxic moiety

•Plays a major role in G –ve bacterial disease
–Endotoxic shock
–Endotoxaemia
–1 ng introduced intravenously = temp > 1 deg C

Question 29

What can toxin do?

Answer 29

–Interfer with cellular processes
•Increase cAMP, stop protein synthesis

–Cause lysis
•Form pores or disrupt membranes

–Hyper activation of processes
•Super antigens, cAMP levels causing fluid imbalances

–Effect neurones at synapses
•Tetanus and botulinum toxin

Question 30

(Role of Toxins in disease) What causes Gangrene and how?

Answer 30

–Causative agent – Clostridium perfringens

•G +ve anaerobic rod

•Infects deep wounds – post operative infections
–Very common before antibiotics

•Produces a variety of secreted factors
–α – toxin – phospholipase C - hydrolyses phospholipids
»Detergent like
–β – toxin – haemolysin
–Collagenase 

•Colonises areas of no blood flow
–Very difficult to treat – defences, drug delivery
–smells bad – production of volatile amines

Question 31

Explain the mode of action of the A toxin of Clostridium perfringens

Answer 31

The enzyme binds to membrane phospholipids and then cleaves the heads away from the tails causing membrane integrity to be compromised and the cell to lyse.

This enzyme basically works a bit like a detergent.

This toxin also can control the movement of immune cells

Question 32

(Role of Toxins in disease) What causes Tetanus and how?

Answer 32

Systemic intoxication caused by Clostridium tetani
•Gram + ve anaerobic rod
•Contaminates deep wounds where O2 concentration is very low

•Produces Tetanospasmin
–Secreted during growth

–Diffuses into neuromuscular synapses

–Blocks release of inhibitory neurotransmitters – glycine

–Induces continuous stimulation and contraction of muscules

–Causes a RIDGID PARALYSIS

–Contraction of the respiratory system leads to death

Question 33

Explain the mode of action of tentanospasmin at the synapse

Answer 33

The toxin prevents the release of inhibitory chemicals causing over stimulation

Question 34

(Role of Toxins in disease) What causes Botulism and how?

Answer 34

Systemic intoxication caused by Clostridium botulinum

•Gram +ve anaerobic rod

•Germination of spores and growth in foods liberates botulinum toxin
–Damaged canned goods, honey, hazelnut yoghurt?

•On ingestion diffuses to neuromuscular synapses

–Blocks release of stimulatory neurotransmitter - acetylcholine

–Induces a FLACCID PARALYSIS

–Death occurs through respiratory/cardiac failure

–May be used medically or in cosmetic surgery

Question 35

Explain the mode of action of Botulinum at the synapse

Answer 35

The toxin blocks the release of stimulatory neurotransmitters leading to a lack of contraction

Question 36

(Role of Toxins in disease) What causes Cholera and how?

Answer 36

Toxigenic disease caused by enterotoxin produced by Vibrio cholera

Gram –ve Comma shaped organism found in faecally contaminated water

–Non-invasive colonisation of the intestinal mucosa

–Cholera toxin secreted and enters cells (A-B toxin)

–Effects c-AMP to cause massive efflux of fluid and electrolytes

–Leads to fatal dehydration

–Fluids and electrolytes need replacing for recovery

Question 37

Explain the mode of action of Cholera Toxin

Answer 37

The toxin interacts with G-coupled proteins to induce the adenylate cyclase enzyme to make huge amounts of cAMP.

This leads to an imbalance of electrolytes which induces massive water loss