DD - Microbial Toxins

Question 1

Definition of microbial toxins

Answer 1

Macromolecular products of microbes that cause harm to susceptible animals by altering cellular structure or function. Most toxic biological substances known are botulinum and tetanus toxins.

Question 2

How are microbial toxins implicated in pathogenesis of IDs?

Answer 2

Traditional methods: 1) show that purified toxin causes the same symptoms or signs as infection by the toxin-producing microbe; 2) show that 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 avirulent and that virulence is restored if the microbe regains the ability to produce toxin

Question 3

Hemolysins and cytolysins

Answer 3

Generally kill target cells. Insert themselves into membranes, assemble into multimeric complexes that form pores, causing lysis of target cells.

Question 4

Lecithinases

Answer 4

Degrade specific cell membrane components, disrupt integrity of the membrane.

Question 5

Superantigens

Answer 5

Most potent known T-cell activators. Bind to MHC-II on APCs and to specific Vb chains on T-cells (not at antigen-binding site) to stimulate excessive production of cytokines (IL-2, INF-gamma, etc.)

Ex. erythrogenic toxins of Streptococcus pyogenes; enterotoxins and TSST-1 of Staphylococcus aureus.

Question 6

Diphtheria toxin

Answer 6

ADP ribosyltransferase; inhibits protein synthesis. Inactivates elongation factor 2 (EF-2) in cytoplasm, required for peptide chain elongation.

Question 7

Pseudomonas aeruginosa exotoxin A

Answer 7

ADP ribosyltransferase; inhibits protein synthesis. Inactivates elongation factor 2 (EF-2) in cytoplasm, required for peptide chain elongation.

Question 8

Shiga toxins

Answer 8

From Shigella dysenteriae, E. coli, plant toxin ricin. RNA N-glycosidases that remove an adenine residue from 28S RNA of 60S ribosomal subunit, inactivating ribosomes to inhibit protein synthesis.

Question 9

Enterotoxins of V. cholerae and E. coli

Answer 9

Modify intracellular signaling pathways. Heat-labile ADP ribosyltransferases; increase adenylate cyclase activity (activates a subunit of stimulatory Gs); results in increased intracellular cAMP in small intestinal enterocytes –> active chloride secretion, secretory diarrhea.

Question 10

Pertussis toxin

Answer 10

ADP ribosyltransferase; modifies intracellular signaling pathways. Increases adenylate cyclase activity (inactivates a subunit of inhibitory Gi). Increased intracellular cAMP causes tissue-specific effects.

Question 11

E. coli enterotoxin I (ST-I)

Answer 11

Modifies intracellular signaling pathways. Heat-stable. Activates guanylate cyclase. Increased intracellular cGMP in enterocytes causes secretory diarrhea.

Question 12

Anthrax edema factor (EF)

Answer 12

Modifies intracellular signaling pathways. From Bacillus anthracis. Adenylate cyclase, enters target cells, increases intracellular cAMP, produces cAMP-dependent effects. Requires activation by calmodulin and calcium (provided by target cells).

Question 13

Adenylate cyclase toxin

Answer 13

Modifies intracellular signaling pathways. From Bordatella pertussis. Adenylate cyclase, enters target cells, increases intracellular cAMP, produces cAMP-dependent effects. Requires activation by calmodulin and calcium (provided by target cells).

Question 14

Anthrax lethal factor (LF)

Answer 14

Modifies intracellular signaling pathways. Endopeptidase; cleaves several MAP kinase kinase proteins to inactivate their function in signal transduction.

Question 15

C. diff toxins A and B

Answer 15

Modify intracellular signaling pathways. Glucosyl transferases; alter actin cytoskeleton by transferring glucose from UDP-glucose to several Rho family GTPases, inactivating them.

Question 16

Botulinum toxin

Answer 16

Inhibits release of NTs. 7 antigenic types (A-G; A, B, and E most common causes disease in humans). Inhibits release of ACh at myoneural junctions; causes flaccid paralysis of skeletal muscles. Zinc-dependent endopeptidase: inactivates VAMP and syntaxin, required for neuroexocytosis.

Question 17

Tetanus toxin

Answer 17

Inhibits release of NTs. Only 1 antigenic type. Inhibits release of NT from inhibitory interneurons in spinal cord; causes sustained muscular contraction. Zinc-dependent endopeptidase: inactivates VAMP and syntaxin, required for neuroexocytosis.

Question 18

Passive immunization against toxin-mediated diseases

Answer 18

Administration of Abs to a patient to provide immediate but temporary protection against toxin or infectious agent

Question 19

Active immunization against toxin-mediated diseases

Answer 19

Administration of toxoid to patient in order to elicit production of specific anti-toxic antibodies. Primary series of immunizations plus periodic booster doses. Active immunity can last for years due to immunologic memory.

Question 20

3 common features of toxins with intracellular targets

Answer 20

1) bifunctional proteins with separate domains or subunits designated A (active) and B (binding)
2) typically use normal membrane constituents as receptors
3) enter target cells by endocytosis: active portion of toxin is translocated to cytosol to interact with target

Question 21

Immunotoxins

Answer 21

Novel therapeutic agents. Hybrid molecules containing active (A) fragment of toxin conjugated to ligands (monoclonal Abs, single-chain Abs, receptor-binding domains of hormones). Eliminates receptor-binding component of native toxin; provides new receptor-binding ability that redirects toxic component to target cells expressing alternative receptor. Designed to kill tumor cells displaying particular tumor-specific receptor but not normal cells that lack the receptor. Potentially valuable in specific cancers, autoimmune diseases.