Microbial Toxins (complete) Flashcards
Define and describe microbial toxins
- Macromolecular products of microbes
- Cause harm to susceptible animals by altering cell structure/function
- Very potent!!
What are the most toxic biological substances known? Give examples
- Clostridial Neurotoxins!
- Lethal dose in the 10^(-5) micrograms (HOLY WOW!)
Ex:
1) botulinum (LD: 2.5x10^(-5) micrograms)
2) tetanus (LD: 4x10^(-5) micrograms)
Which traditional methods show that a specific toxin has a role in pathogenesis?
1) Purified toxin causes same symptoms/signs as infection by the toxin-producing microbe
2) Antitoxin prevents disease caused by the toxin-producing microbe
3) Virulence of individual bacterial strains correlates w/ amount of toxin produced
4) Non-toxinogenic mutants are avirulent — virulence restored if microbe regains ability to produce toxin
Describe the molecular version of Koch’s postulates
1) Specific phenotype is associated with pathogenic species
2) Inactivation of a specific gene(s) encode for putative virulence factor — causes a measurable decrease in virulence of the microbe
3) Replacement of mutated gene by wild type allele restores virulence of the microbe to original, wild-type level
Describe the composition and properties of bacterial protein toxins
- Usually heat-labile
- Immunogenic
- Neutralized by specific Abs
Some secreted into culture medium (diphtheria)
Some released by bacterial lysis
Describe the composition and properties of lipopolysaccharides (LPS) of g(-) bacteria
- LPS is a PAMP
- Therefore —> recognized by the innate immune system –» elicits a host response
- Low LPS doses activate macros, B-cells, alternative complement pathway —» fever, inflammation
- High LPS doses —» shock, DIC
What are the 6 classifications for bacterial protein toxins based on their mechanisms of action?
Toxins that…
1) Facilitate spread of microbes through tissues
2) Damage cellular membranes
3) Stimulate cytokine production
4) Inhibit protein synthesis
5) Modify intracellular signaling pathways
6) Inhibit neurotransmitter release
Describe how toxins facilitate the spread of microbes through tissues
- Some toxic enzymes break down ECM
- Some degrade debris in necrotic tissue
This ENHANCES spread of microbes
Describe how toxins damage cellular membranes
- Called cytolysins
- These insert into membranes and assemble into multimeric complexes —»> form pores
- This causes lysis of target cells
Others degrade specific cell membrane components/disrupt membrane integrity
Describe how toxin stimulate cytokine production
- Super Ags!
- Most potent known T cell activators
- Bind to MHC Class II and V(beta) chains on T cells
- Activate larger numbers of T cells
- Causes excessive cytokine production —-» pathogenic probs!!
Describe how toxins inhibit protein synthesis. What are two toxins that do this?
Diphtheria:
inactivates EF-2 (this is required for peptide chain elongation— no EF2? Cell death for you!)
Shiga:
Removes a particular adenine residue from ribosomes —»> inactive ribosomes, no more translation
Describe how heat-labile enterotoxins of cholera and E coli modify intracellular signaling pathways
Activates alpha subunit of G(s) reg protein —-» increases intracellular cAMP in small intestine
Causes: active Cl secretion, secretory diarrhea
Describe how pertussis toxin modifies intracellular signaling pathways
Inactivates alpha subunit of G(i) reg protein —» increases intracellular cAMP —» tissue-specific effects
Describe how heat-stable enterotoxin I of E. coli modifies intracellular signaling pathways
Activates cell-membrane associated guanylate cyclase
Increase cGMP in enterocytes —-» secretory diarrhea
Describe how anthrax edema factor and adenylate cyclase toxin modify intracellular signaling pathways
Adenylate cyclases enter target cells —» increase intracellular cAMP
Enzyme activity requires activation by calmodulin and calcium
Describe how anthrax lethal factor modifies intracellular signaling pathways
Inactivates MAP kinase kinase proteins
Not exactly known how this contributes to lethal effects of LF
Describe how C. Diff toxins A/B modify intracellular signaling pathways
Alters actin cytoskeleton of target cells
Inactivates Rho family GTPases
Describe how botulinum toxin inhibits neurotransmitter release
Inhibits release of Ach at myoneural junctions —»> paralysis of skeletal muscles
Used as a treatment for dystonias/involuntary movement disorders
Describe how tetanus toxin inhibits neurotransmitter release
Inhibits NT release from inhibitory interneurons in spinal cord —-»> sustained muscular contraction of skeletal muscles
Describe how zinc-dependent endopeptidases inhibit neurotransmitter release
Inactivates specific SNARE proteins required for neuroexocytosis
Toxins with intracellular targets must cross the plasma membrane before they can exert their toxic effects. What are the 3 common features of these types of toxins?
1) Usually bi-functional proteins w/ separate domains/subunits designated for active sites and binding sites
2) Typically use normal membrane constituents as receptors
3) Usually enter target cell by endocytosis
What are the 4 ways to prevent/treat toxin-mediated disease?
1) Antitoxic Abs
2) Toxoids
3) Passive IZ
4) Active IZ
Describe how antitoxic Abs are used to treat toxin-mediated disease
- Bind to toxins —» neutralize their toxicity
- Do not prevent infection
- Do not reverse toxic effects
Describe how toxoids are used to prevent toxin-mediated disease
- Derivatives of toxins — retain immunogenicity, but are not toxic
- Used as vxs for long-term protection
Describe how passive IZ is used to prevent toxin-mediated disease
- Provides temporary protection from disease (think breastfeeding)
- Duration of immunity limited by degradation of Abs in the pt
Describe how active IZ is used to prevent toxin-mediated disease
- Involves administration of toxoid to a pt —» elicits anti-toxic Abs production in pts
- These vxs are used as a series (and have booster doses)
- Active immunity can last for many years b/c of immunologic memory
What are immunotoxins?
- Hybrids of toxin fragment (lacks receptor-binding domain) and a ligand
- Binds to a different receptor that the original native toxin
- Intoxicates alternative receptor
How are immunotoxins used as therapeutic agents?
- Designed to kill tumor cells that display tumor-specific receptors
- Goal: not to kill normal cells (that don’t have this receptor)
Also used in autoimmune disease
