Microbial Toxins Flashcards
Definition
macromolecular products of microbes that cause HARM to SUSCEPTIBLE animals by ALTERING CELLULAR STRUCTURE OR FUNCTION
Explain how a microbial toxin is implicated in pathogenesis of an infectious disease
Show that…
- Purified toxin causes the same symptoms or signs as infection by the toxin-producing microbe.
- Antitoxin prevents disease caused by the toxin-producing microbe.
- Virulence of individual bacterial strains correlates with the amount of toxin that they produce.
- Nontoxinogenic mutants are avirulent and that virulence is restored if the microbe regains the ability to produce toxin.
One a molecular level (Koch), show that:
- The toxin-producing phenotype is associated with a specific species/strain
- If you KO the gene encoding the toxin, you decrease the microbe’s virulence.
- The, if you replace the gene, virulence is restore to the original WT level.
Describe exo and endotoxins
EXO: found OUTSIDE bacterial cells. Generally heat-labile, immunogenic, and neutralized by Abs; can be secreted or released upon lysis
ENDO = LPS;
- Host response via LPS binding protein, CD14, TLR4, and other signal transduction molecules.
- Low doses activate macs, B-cells and the Alt. complement pathway –> fever, production of acute phase reactants, polyclonal Ab synthesis, inflammation.
- High doses cause shock and disseminated intravascular coagulation.
- Many of the biologic effects of LPS are mediated by cytokines.
What are 6 ways toxins can affect a host?
- Facilitate spread of microbes thru tissues
- Damage cell membranes –> kill cells (hemolysins and cytolysis); some form pores, others simply disrupt integrity
- Stimulate cytokine production –> pyrogenic (cause fever, food poisoning, TSS. THESE ARE SUPERANTIGENS!!
- Inhibit protein synthesis
- Alter signaling pathways
- Inhibit NT release
Diphtheria toxin / Pseudomonas aeruginosa exotoxin A
- Protein synth inhibitor
- Inactivate elongation factor 2 (EF-2), which is required for peptide chain elongation.
- ADP ribosyltransferases that transfer ADP-ribose from nicotinamide adenine dinucleotide (NAD) to a modified histidine residue called diphthamide on EF-2, thereby inactivating EF-2 in the cytoplasm.
- Classic presentation is kid with lesion on back of throat
Shiga (from Shigella dysenteriae and E. coli)
- Protein synth inhibitor
- Highly specific RNA N-glycosidases that remove one particular adenine residue from the 28S RNA of the 60S ribosomal subunit, thereby inactivating the ribosomes.
- Same mechanism as ricin
Vibrio cholerae and E. coli
- Modify intracellular signaling
- Heat-labile enterotoxins are ADP ribosyltransferases that increase adenylate cyclase activity (on PM) by ADP-ribosylating and ACTIVATING the α subunit of the STIMULATORY Gs regulatory protein of the cyclase complex. Increased intracellular cAMP in small intestinal enterocytes causes active chloride secretion and results in secretory diarrhea.
Pertussis toxin
- Modify intracellular signaling
- ADP ribosyltransferase that increases cell membrane-associated adenylate cyclase activity by ADP-ribosylating and INACTIVATING the α subunit of the INHIBITORY Gi regulatory protein of the cyclase complex. Increased intracellular cAMP causes tissue-specific effects
Heat-stable enterotoxin I (ST-I) of E. coli
- Modify intracellular signaling
- Activates cell membrane-associated guanylate cyclase. Increased intracellular cGMP in enterocytes also causes secretory diarrhea.
Bacillus anthracis Anthrax edema factor (EF) &
Bordetella pertussis’ Adenylate Cyclase toxin
- Modify intracellular signaling
- Adenylate cyclases that enter target cells, cause intracellular cAMP to increase, and produce cAMP-dependent effects. Their enzymatic activity requires activation by calmodulin and calcium, which are provided by the target cells.
Anthrax lethal factor (LF)
- Modify intracellular signaling
- Endopeptidase that cleaves several MAPKK proteins and inactivates their function in signal transduction. It is not yet know precisely how inactivation of this signal transduction pathway contributes to the lethal effects of LF.
C. diff A & B
- Modify intracellular signaling
- Glucosyl transferases that alter the actin cytoskeleton of target cells by transferring glucose from UDP-glucose to several Rho family GTPases (including Rho, Rac and Cdc42), thereby inactivating them.
Botulinum toxin (7 antigenic types, A-G)
- Inhibit NT release
- causes FLACCID paralysis of skeletal muscles
- inhibits ACh release @ myoneural junctions.
- A, B, E most often cause disease in humans
Tetanus toxin
- Inhibit NT release
- causes sustained muscular CONTRACTION (tetany) of skeletal muscles
- inhibits release of neurotransmitter from INHIBITORY interneurons in the spinal cord.
Tetanus toxin and the botulinum toxins are ____-dependent endopeptidases. They inactivate specific _______ proteins required for _____________ [VAMP (also called synaptobrevin), the 25 kDa synaptosome-associated protein (SNAP-25), and syntaxin].
Zinc
SNARE
neuroexocytosis
Each toxin cleaves one specific protein (VAMP/synaptobrevin, SNAP-25, syntaxin) at one specific site; variable cleavage across serotypes
