BIOL 2421 Microbiology Virulence Factors: Exotoxin and Endotoxin comparison
|
Name |
Exotoxin |
Endotoxin |
|
Source |
Gram (+) and G(-) bacteria |
G (-) bacteria |
|
Location |
Released from cell |
Integral part of cell wall |
|
Type |
Protein |
Lipid A of LPS |
|
Number |
Many |
One |
|
Stability |
Heat Labile, denatured by boiling |
Heat Stable, not denatured by boiling |
|
Target |
Specific host receptors |
Diverse range of targets |
|
Effects |
Specific effects |
Diverse effects, less specific [can be system wide] |
|
Enzymatic Activity |
Usually |
No |
|
Antigenic |
Yes |
Yes |
|
Potency |
Relatively high |
Relatively low |
|
Treatment / Prevention |
Toxoids made by treating with formalin |
Toxoids cannot be made |
Bacterial Exotoxins
2 broad classes
A. Intracellular Targets: A-B dimeric (two domain) exotoxins
B. Cellular Targets: Cytolysins / Cytolytic
Intracellular Target Exotoxins
A-B structure =
B for binding, associated with target cell and transfer of active across the cell membrane
A for active portion of molecule, once internalized will enzymatically disrupts cell function
Types of A*B toxins
I> ADP-ribosyl transferases : stops protein synthesis
^ Diptheria Toxin of Corynebacterium diptherium
^ Exotoxin A of Pseudomonas aeruginosa
^ Cholera Toxin of Vibrio cholerae
^ Labile Toxin [LT] of E. coli
^ Bordetella pertussis toxin of Bordetella pertussis
II> Non Ribosylating Toxins
^ Shiga Toxin of Shigella
binds to human 60S ribosomes
^ Anthrax Toxin of Brucella anthracis
Protective antigen (PA) à binds
Edema Factor (EF) à adenylate cyclase
Lethal Factor (LF) à tissue necrosis
^ Tetanus toxin of Clostridia tetani
blocks release of inhibitory (GABA) neurotransmitter by preventing vesicle formation
à results in muscle spasm
^ Botulinum toxin of Clostridrium botulinum
blocks
release of Ach @ NMJ by preventing neurotransmitter vesicle formation à muscle paralysis
^ Pycocyanin of Pseudomonas aeruginosa
binds to flavoproteins of cytochrome system
interferes with
electron transport
^ Adenylate Cyclase Toxin of Bordetella pertussis
catalyzes conversion of ATP to cAMP
inhibits WBC
^ NAD glycohydrolase Toxin of Shigella flexneri
rapidly depletes NAD of phagocyte to block
cell metabolism à killing phagocyte
Cellular Targets for Exotoxins
* Trachea Toxin of Bordetella pertussis
kills cilia bearing cells of trachea
* Beta Toxin of Clostridium difficle
necrotic enteritis
* Exfoliating Toxin of Staphylococcus aureus
sloughing of skin
* TSST [Toxic Shock Syndrome Toxin] of Staphylococcus aureus
Il-1 mediated reaction à fever à rash à capillary changes à
Desquamation of skin
* Erythrogenic Toxin of Streptococcus pyogenes
same MOA as TSST
* Mycolactone Toxin of Mycobacterium ulcerans
skin and muscle necrosis
Bacterial Endotoxins
LPS = consists of 4 regions:
Region III + Region IIb with Regions IIa + Region I
Region I = Lipid A
Region II a and II b = Core ( R ) antigens
Region III = Somatic (O) antigen or O polysaccharide
O-specific chain + Outer Core and Inner Core + Lipid A
Lipid A contains the saturated Fatty acid [lipid] component of the molecule
The Core contains short chain of sugars and is common to all members of
a bacterial genus, but is different and distinct in other genera of G(-)
The O antigen side chain consists of repeating sugar chains that vary in length
Presence of an O side chain give a colony a smooth appearance, while loss of the O specific region results in the strain becoming rough in appearance.
Both the Lipid A and the polysaccharide chains of the LPS help determine virulence.
O polysaccharides
*Adherence to epithelial tissue
* Reistance to phagocytosis
* Carriers for toxic Lipid A
* Protect from complement reactions [fails to have normal lytic effect]
* Antigenic variation à multiple
serotypesà multiple types of infection
Core
*Determines permeabililty of outer membrane
* Less susceptible to antibiotics, detergents, bile
salts
Lipid A
· Mediates the physiological effects of the endotoxin
· Begins with CD 14 binding of receptors on Macrophages that:
Induces cytokine production: Il-1, Il-6, Il-8, TNF, PAF, PG
Activation of complement cascade (C3a, C5a or alternate pathway)
Activation of coagulation cascade (Factor XII)
Toxic Action of LPS
a) Fever (inflammatory mediators
released, Il-1)
b) WBC count (macrophages increase phagocytosis)
c) Clearing of fibrin polymers @ inflammatory site
causing hemorrhagic necrosis
c) DIC (due to activation of coagulation)
d) TNF (produced by macrophages to destroy cells)
e) Hypotension (due to vasoactive peptide release)
f) Shock (loss of fluids, ie diarrhea, vomiting)
g) lethal (i.e death)
Other Virulence Factors:
A) Capsule [K antigen]
Primarily polysaccharide, some have AA/protein
Prevent phagocytosis
Prevent lysis by lysosomes or complement mediated activity
Prevent leukocyte migration [paralyzes WBC]
Allows adhesion to host cell
Protects anaerobes from O2 toxicity
Receptors for bacteriophages
B) Pili / Fimbria
Anchored to plasma membrane and protrudes through cell wall
F pili produced by male bacteria to allow binding during conjugation
Type I and II pili [fimbria]
promote adhesions to human cells
C) Flagella [H antigen]
Locomotion to evade phagocytosis
Enable bacteria to come close to adhesion receptors on host cell
Used to help serotype bacterial strains
D) Endospore
Resist adverse conditions
E) Plasmids
Code for virulence factors such as AB resistance