Toxins Flashcards
Exoenzymes
Secreted bacterial effector molecules
Aid in invasion and evasion of the immune response
Examples
- streptokinase
- coagulase
- hyaluronidase
Exotoxins
Can be released by gram (+) and gram (-)
Are secreted proteins/polypeptides
Have specific MOA
Majority are heat-liable
LD50 is low
Highly antigenic (can make a toxoid vaccine)
Endotoxins
Gram (-) organisms only
Most common = LPS/LOS on the bacterial cell walls
Produces general systemic symptoms of inflammation and fever
Majority are heat-stable
LD50 is very high
Weakly antigenic (cant make a toxoid vaccine against)
What is a toxoid vaccine
Modified toxins that are still antigenic but lack virulence
- great to build antibodies against without producing a disease state
3 subtypes of exotoxins
Type 1: membrane-acting toxins
- bind to host cell surface receptors and stimulate transmembrane signals
- examples = some enterotoxins, superantigens, etc.
Type 2: membrane-disrupting toxins
- act as host cell membrane proteins and exert effects by damaging the cell membranes
- examples = pore-forming toxins, phodspholipases, some enterotoxins
Type 3: intracellular-acting toxins
- act by binding a region on the toxin to specific cellular receptors to get inside cell. Then act on intracellular target molecules
- examples = A-B toxins, some enterotoxins
Enterotoxins
Refer to protein toxins that cause diarrhea or vomiting
- host target cells are intestine cells
Type 1 examples
- staphylococcal enterotoxins (A-E)
- Heat-stable enterotoxin A and B (from E.coli)
Type 2 examples:
- clostridium perfringens enterotoxin (CPE)
- streptomycin O/S from strep pyogenes
- phospholipase CH from pseudomonas
- listeriolysin O from L. Monocytogenes
Type 3 examples:
- cholera toxin
- diphtheria toxin A/B
- C. Diff toxins A/B
- Shiga toxins 1/2
Heat stable enterotoxin A (STa)
Produced by ETEC e.coli
Is NOT a super antigen
Binds to guanylin uroguanylin receptors and upregulates cAMP/cGMP and PKA levels
- end goal = permanently opens bicarbonate and chloride symporter opening which releases these into the GI tract while also inhibiting H+/Na+ exchangers
- results = extreme electrolyte secretion and impaired water absorption = watery diarrhea
Superantigens
Bind to MCH and TCRs and doesn’t release them (glues them)
- results in excessive cytokine release and polyclonal T-cell activation
Cytokines released by TCR binding (<1%)
- IFN-y/ IL-12 if TH1 cell
- IL-4/IL-5 if TH2 cell
- IL-17/IL22 if TH-17 cell
Cytokines released by class 2 MHC biding (20-60%) - IL-2/IFN-y and TNF-a
What two syndromes are common superantigen syndromes
TSS
- staph induced = TSST-1 or enterotoxin B
- step induced = strep exotoxin A/B
Scarlet fever
- strep pyogenic exotoxins A/B/C
Type 3 A/B toxin structure
A = activity subunit
- interacts with intracellular process and is released from subunit B at the extracellular receptor
B = binding subunit
- interacts with the extracellular receptors and allows A subunit inside
Diphtheria toxin
Produced by Clostridium diphtheria
A subunit = ADP-ribosyltransferase activity
- catalyzes a reaction between NAD+ and elongation factor 2 (EF2)
- results in covalent attachment of ADP-ribozymes to EF-2 causing its inactivation leading to cell death
Shiga toxin 1/2 (Stx1 and Stx2)
Is produced by STEC e.coli and shigella species
Subunit depurinates the 28rRNA in the 60s subunit of the ribosomal complex
- creates “ribotoxic stress responses” which is pro inflammatory and pro apoptosis
- results in decreases in sodium absorption and damage to endothelial cells
Cholera toxin
type 3 enterotoxin A-subunit has ADP-ribosyltranserfrase activity
- this targets a Gs protien in intestinal mucosal cells which results in Ionic imbalance and water secretion
- results in massive sodium chlride and water outflow of the cells = watery diarrhea
Pertussis toxin
Type 3 toxin that is produced by B. Pertussis
A-subunit has ADP-ribosyltransferase
- targets Gs-proteins in Lung cells and induces a bunch of actions but primarily exports potassium out of cells
Anthrax toxin
Type 3 toxin Produced by B. Anthracis
Edema factor functions to elevate intracellular cAMP and calmodulin-dependent adenylate Cyclase
Lethal factor = cleaves enzymes in MAPK signaling which impairs enzyme functions
- endothelial cells undergo apoptosis due to this
How does tetanospasm work?
Type 3 toxin that cleaves synaptobrevin in inhbitor synapses and prevents GABA vesicle releases
**Botulinum has the same effect except prevents ACh release by cleaving SNARE proteins
LPS vs LOS based on structure
Both have similar actions except LOS has no O-antigen
- LPS does have this antigen
the O-antigen is variable
LPS is known to activate numerous immune mechanisms and clotting pathways
- LPS binds to PRRs (TLR4) and stimulates an extraordinary range of host receptors
Both contain Lipid A and core oligosaccrhides
What is the major inflammatory cytokine responsible for septic shock?
TNF-a
- synergized by the effects of IL-1B and IRN-y also
Organisms that can cause endotoxin-like shock
Organisms that can cause endotoxin like shock
- gram (-) via LPS
- staph via TSST1
- B. Pertussis via endotoxins
- yeasts via zymogen
- plasmodium species via phospholipids
Gram (+) and of these other species go through the TLR2 pathway to activate TNF-a
Gram (-) goes through TLR4 pathway to produce TNF-a
Fungi and protozoan also use TLR-4
