Flashcards in Microbial Toxins Deck (28):
What are microbial toxins?
=Macromolecular products of microbes, which cause harm to susceptible animals by altering cellular structure or function
What are the most potent microbial toxins?
(clostridium neurotoxins, including tetanus)
Why worry about microbial toxins? What conditions can they cause?
Botulism, cholera, diphtheria, whooping cough, scalded skin syndrome, scarlet fever, tetanus, and TSS
-Infectious diseases cause 1/3 of deaths globally
-Infectious diseases cause 48% of deaths in ppl
What are the traditional methods to show that a microbial toxin is causing a disease? (there's four)
1. Show that purified toxin causes the same symptoms as infection by the toxin-producing microbe
2. Show that an antitoxin prevents disease caused by the toxin-producing microbe.
3. Show that virulence of individual bacterial strains correlates with the amount of toxin that they produce.
4. Show that nontoxinogenic mutants are less virulent, and that virulence is restored if the microbe regains the ability to produce toxin.
Very nice. But we can't ethically prove those things using human subjects... so how can we use a molecular version of Koch's postulates to prove that a toxin causes disease? (three things)
1. Show that the toxin production is associated with a pathogenic species or with pathogenic strains of a microbe.
2. Show that inactivation of a specific gene(s) that encodes the supposed virulence factor causes a measurable decrease in virulence of the microbe.
3. Show that replacement of the mutated gene by the wild type allele restores virulence of the microbe to the original, wild type level.
Can you name 6 mechanisms of action for microbial toxins?
1. Toxins that facilitate spread of microbes through tissues
2. Toxins that damage cellular membranes
3. Toxins that stimulate cytokine production
4. Toxins that inhibit protein synthesis:
5. Toxins that modify intracellular signaling pathways
6. Toxins that inhibit the release of neurotransmitters
Let's start from the top. What are some toxins that facilitate spread of microbes through tissue? How do they work?
hyaluronidase, collagenase, elastase, deoxyribonuclease, and streptokinase, etc.
These are enzymes releases by microbes to break down extracellular matrix or degrade debris in necrotic tissue, thereby enhancing spread of microbes
How can some toxins damage cell membranes?
-Cell death from inserting into membranes and assemble into multimeric complexes that form pores, thereby causing lysis of target cells
-Others degrade specific cell membrane components and disrupt the integrity of the membranes
What is a hemolysin?
-Membrane damaging toxin (cytolysin) on erythrocytes
Can you give an example of a pore forming structure from a microbe?
α-Hemolysin of Staphylococcus aureus can make a pore-forming complex
What mechanism of action do pyrogenic exotoxins use?
=stimulate cytokine production. They belong to a class of super antigens
How do super antigens work?
-stimulate excessive production of cytokines
-they activate much larger numbers of T cells than any specific antigen does.
-They act by binding both to major histocompatibility (MHC) class II molecules on antigen-presenting cells and to specific chains on T cells at a site that is different from the antigen-binding site
What are some examples of pyrogenic exotoxins and what can they cause?
=erythrogenic toxins of Streptococcus pyogenes and the enterotoxins and toxic shock syndrome toxin (TSST-1) of Staphylococcus aureus
Can cause scarlet fever, food poisoning, and toxic shock syndrome
What are some toxins that inhibit protein synthesis?
-Diphtheria toxin (DT)
-Pseudomonas aeruginosa exotoxin A (PAE)
-Shiga toxins of Shigella dysenteriae and E. coli
-Ricin (plant toxin)
T/F: DT and PAE have the same mechanism of action?
True and false...
They both target and inactivate elongation factor 2 (EF-2) but do so by entering the cell through different receptors/ processes
***So one doesn't immunize you against the other
A toxin inhibited EF-2 in the liver. Which one was it?
PAE receptors are mostly on liver cells
DT are only on heart, kidney and neurons
How does Shiga toxins and Ricin inhibit protein synthesis?
They are RNA N-glycosidases that remove one particular adenine residue from the 28S RNA of the 60S ribosomal subunit,
List toxins that modify intracellular pathways.. (just to organize it in your head)
1. Heat-labile enterotoxins (LTs) of cholerae and E. coli
2. pertussis toxin
3. Heat-stable enterotoxin I (ST-I) of E. coli
4. Anthrax edema factor (EF)
5. Anthrax lethal factor (LF)
6. Clostridium difficile
T/F: Heat-labile enterotoxins (LTs) of Vibrio cholerae and E. coli cause direct damage to epithelial cells?
Activate subunit of Gs protein in GI epithelial cells>> increases cAMP >> causes active Cl- secretion >>> diarrhea
T/F: pertussis also activates Gs protein to increase cAMP?
Except this occurs in neutrophils and macrophages to inhibit phagocytosis
Which toxin increases cGMP to cause diarrhea?
Heat-stable enterotoxin I (ST-I) of E. coli
What toxin requires activation by calmodulin and calcium (from host)?
-Anthrax edema factor (EF)
Also increase cAMP in cardiomyocytes and smooth muscle/endothelial cells for lethal effects
Name the two toxins that inhibit release of neurotransmitters? Which one causes flaccid paralysis?
Botulinum toxin- flaccid paralysis of muscles
Tetanus toxin- spastic/tetanic/rigid paralysis
What do botulism and tetanus toxins have in common? What is different?
Common = Both have zinc-protease activity
Different = location
>Botulism: inhibits acetylcholine at motor neuron
>Tetanus: inhibit acetylcholine at spinal Interneuron
How can you prevent toxin-mediated disease?
1. Antitoxic antibodies (antitoxin) can neutralize specific toxins extra-cellularly (before the toxin enters target cells)
2. Many protein toxins can be converted to toxoids that are useful as vaccines
=Active immunization (long lasting)
T/F: can you use toxins therapeutically?
This should be an obvious yes.
Immunotoxins & hormonotoxins -
Immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to a cell, it is taken in through endocytosis, and the toxin kills the cell.
=> Use DT + IL-2 to treat T-cell lymphomas
There were five slides on endotoxin... so what is it?
Lipopolysaccharide (LPS) on gram (-) cells
-Sepsis & septic shock
-Can activate Hageman Factor XII (fibrinolysis & hypotension from bradykinin)