Microbial Toxins Flashcards
Molecular version of Koch’s Postulates
- Show toxin production is associated with pathogenic species / strain of microbe.
- Show inactivation of virulence factor gene –> decreased virulence
- Show replacement of mutated gene w/ wild type allele restores wild type virulence levels
Two main categories of Microbial Toxins
- Bacterial Protein Toxins
2. LPS of Gram Negative bacteria
General properties of Bact. Protein toxins
- heat-labile
- immunogenic
- neutralized by specific Ab
“Exotoxins” = secreted or spilled at lysis
General properties of LPS toxins
- is a PAMP - recog. by TLR4
- Response pathway involves LPS binding protein, TLR4, CD14 + other.
- Low Dose - fever, acute phase inflamm., polyclonal Ab production, activate Macs, B-cells, alternative complement pathway
- High Dose - Shock, DIC, cytokine mediated effects
Toxic enzymes such as hyaluronidase, collagenase, elastase, deoxyribonuclease and streptokinase act by…
break down extra cellular matrix and degrade debris, enhancing spread of microbe.
Toxins that damage cell membranes usually do what to cells…
kill them
Fancy names for toxins that damage cell membranes…
hemolysins - so named b/c seen to lyse RBCs
Lecithinases
Cytolysins - lyse a variety of cells
Action of Cytolysins…
insert into membrane, form pore –> lysis
Action of Lecithinases
degrade cell membrane components, disrupt membrane integrity
Toxins that stimulate cytokine production…fancy name.
Superantigens
ex: Pyrogenic exotoxins
Superantigen Action
Bind MHC II and T-Cells (V_beta chain)
Activate LOTS of T Cells,
Cytokine release (excessive) IL-2, IFN-gamma
Diphtheria Toxin & Pseudomonas aeruginosa Exotoxin A action…
ENTER CELL
inactivate elongation factor 2 (EF-2) thus INHIBIT PROTEIN SYNTHESIS
Are ADP ribosyltransferases: transfer ADP-ribose from NAD to modified histidine residue (diphthamide) of EF-2, thus inactivating EF-2
Shiga toxin is released by which two microbes?
Shigella dysenteriae
E. Coli (gram neg. rod :)
Shiga toxin action
RNA N-glycosidases
remove a particular adenine residue from 28S RNA of 60S rib. subunit –> inactivate ribosomes –> INHIBIT PROTEIN SYNTHESIS
What plant toxin has the same action as Shiga toxin?
Ricin
Name 7 toxins that alter intracellular signaling pathways.
- Heat-labile enterotoxins of Vibrio cholerare and E. Coli
- Pertussins toxin
- Heat-stable enterotoxin I (ST-I) of E. Coli
- Anthrax edema factor (EF) of Bacillus anthracis 5. Adenylate cyclase toxin from bordetella pertussis
- Anthrax lethal factor (LF) from bacillus anthracis
- C. diff- toxins A & B
Action of Heat-labile enterotoxins of Vibrio cholerae and E. coli
ADP ribosyltransferases —> activate alpha subuint of stimulatory G_s regulatory protein –>increased intracellular cAMP in small intestinal enterocytes –> active chloride secretion —> secretory diarrhea
Action of Pertussin toxin (PTx)
ADP ribosyltransferase –> inactivate alpha subunit of inhibitory G_i –> increased intracellular cAMP –> tissue specific effects
End Result: inhibit host immune response. e.g. prevent phagocytosis, prevent lymphocytes from entering lymph nodes resulting in lymphocytosis
Action of Heat stable enterotoxin I (ST-I) of E. coli
Activate cell membrane-assoc. guanylate cyclase. increase intracellular cGMP in enterocytes –> secretory diahhrea
Action of Anthrax edema factor (EF)
Bacillus anthracis.
Requires what host-cell contents to activate?
Adenylate cyclases
enter target cells
increase intracellular cAMP –> cAMP dependent effects
REQUIRES ACTIVATION BY CALMODULIN AND CALCIUM
Action of Bordetella pertussis adenylate cyclase toxin (PTx) requires what host-cell contents to activate?
same as Anthrax EF
increase cAMP –> cAMP-dependent effects
REQUIRES ACTIVATION BY CALMODULIN AND CALCIUM
Action of Anthrax lethal factor (LF)
endopeptidase
cleaves MAP kinase kinase proteins, inactivates their fn. in signal transduction
…contribution to lethal effects in cardiac muscle cells and vasculature.
Action of C. diff toxins A & B
glucosyl transferases
alter actin cytoskeleton
transfer glucose from UDP-glucose to Rho family GTPases —inactivating them
Action of Botulinum toxin…how many antigenic types and which ones cause dx in humans?
Flaccid paralysis (skeletal muscles) inhibit Ach release and myoneural junction
A,B,E cause dx
Action of Tetanus toxin.
How many antigenic types?
Contractile paralysis
inhibit neurotransmitter release at inhibitory interneurons in spinal cord
only one antigenic type
Tetanus toxin and botulinum toxins have this in common…
zinc-dependent endopeptidases
inactivate SNARE proteins –> inhibity neuroexocytosis (VAMP = synaptobrevin, SNAP-25 and syntaxin) via serotype-specific protein cleavage
(thankyou Dr. Prekeris)
How is Botulinum toxin used therapeutically?
tx: focal dystonias (e.g. parkinsons pts on certain meds experience this as a side effect and get botox injections as tx)
also, cosmetic
Toxins that act intracellularly have what general structure?
bifunctional proteins with separate domains (subuints)
A = active domain
B = binding domain
Susceptibility / Resistance of a target cell to a specific toxin depends on what?
presence or absence of receptors on cell membrane
What do toxins generally use as receptors?
they’ve evolved to take advantage of normal membrane constituents.
What does diptheria toxin use as its cell receptor?
heparin-binding EGF-like growth factor precursor
What does P. aeruginosa_exotoxin A use as its cell receptor?
alpha2-macroglobulin receptor / LDL-receptor-related protein (LRP)
What does diptheria toxin and P. aeruginosa_exotoxin A have in common / different?
same intracellular actions but act on different cell types based on expressed cell receptors.
What is the receptor for E. coli heat labile enterotoxin?
ganglioside GM1
glycolipid
What is the receptor for Shiga toxin?
glycolipid Gb_3
How do toxins usually enter cells after interacting with their receptor?
Endocytosis
After endocytosis how do toxins
Diptheria toxin, anthrax toxin, buotulinum toxin and tetanus toxin
usually proceed in action?
Active portion of the toxin is translocated to the cytosol to interact with its target.
change in conformation of translocation domain in response to acidic endosomes
inserts, forms pore–> active domain released to cytosol
After endocytosis, how do toxins
Shiga toxin, exotoxin A of Pseudomonas aeruginosa, cholera toxin, pertussis toxin
usually proceed in action?
no translocation domain
traffic thru retrograde pathway
endosomes–> golgi –> ER
in ER active component released and translocated to cytosol by translocon (ERAD pathway of host)
Examples of SUPER ANTIGENS
- pyrogenic exotoxin: erythrogenic toxins of Strep. pyogenes
- enterotoxins and TSST-1 of Staph. aureus.
Some diseases caused by the superantigens of S. pyogenes and S. aureus
Scarlet fever, food poisoning, TSS.
