Microbial Toxins Flashcards
Define “Microbial Toxins”
Microbial toxins are macromolecular products of microbes that cause harm to susceptible animals by altering cellular structure or function.
What are the most lethal toxins known?
Botulinum A, Tetanus, Shiga, Diphtheria, Staph enterotoxin B, Staph alpha
Why are microbial toxins important?
Some toxins cause major manifestations of specific diseases, such as botulism, cholera, diphtheria, scalded skin syndrome, etc. Other toxins contribute to pathogenesis without causing uniques signs or symptoms. Also, toxin-mediated diseases cause significant morbidity and mortality, especially in developing countries.
What is the traditional method for showing that a specific toxin has a role in pathogenesis of a disease?
1) Show that the purified toxin produces the same signs and symptoms as infection by the microbe. 2) Show that anti-toxin prevents disease caused by the microbe. 3) Show that virulence of individual bacterial strains correlates with the amount of toxin they produce. 4) Show that nontoxinogenic mutants are avirulent and that virulence is restored if the microbe regains the ability to produce the toxin.
What is the molecular version of Koch’s Postulates?
1) Show that the phenotype or pretor to be investigated (toxin production) is associated with a pathogenic species or with pathogenic strains of the microbe. 2) Show that inactivation of a specific gene(s) that encodes the putative virulence factor causes a measurable decrease in virulence of the microbe. 3) Show that replacement of the mutated gene but the wild type allele restores virulence of the microbe to the original, wild type level.
How are the structure and function of microbial toxins categorized?
Microbial toxins are categorized by their composition and properties, their mechanisms of action, and by their mechanisms and pathways for entry into cells.
What are the two classes of toxin composition?
Protein toxins, such as diphtheria and botulism toxins, are heat-labile, immunogenic, and neutralized by anitbodies. Some are excreted (diphtheria) and some are released by cell lysis (botulism). Lipopolysaccharides (LPS) of gram-negative bacteria are PAMPs and activate the innate and adaptive immune systems. Low doses activate macrophages, B-cells, and alternative-pathway complement. High doses of LPS cause shock and DIC.
What are the six mechanisms of action that microbial toxins use?
1) Facilitate the spread of microbes through tissues. 2) Damage cellular membranes. 3) Stimulate cytokine production. 4) Inhibition of protein synthesis. 5) Modify intracellular signaling pathways. 6) Inhibit the release of neurotransmitters.
How do some toxins facilitate the spread of microbes through tissues?
By breaking down the ECM or degrading debris in necrotic tissue, allowing the microbes to spread through them. Hyaluronidase, collagenase, elastase, etc.
How do some toxins damage cellular membranes?
Many membrane damaging toxins insert into membrane and assemble into complexes that form pores, lysing the cell. Others degrade specific membrane components, and disrupt the integrity of the membrane. They are hemolysins or cytolysins, depending on the cells they target.
How do toxins that stimulate cytokine production cause harm to the host?
Toxins that stimulate cytokine production include the pyrogenic exotoxins of Strep pyogenes and enterotoxins causing toxic shock syndrome of Staph aureus and are part of a larger class called super antigens. They bind both the MCH II of APCs and Vb of T-cells at a site that is different from the antigen binding site and activate a large number of T-cells. They thus stimulate excessive production of cytokines (inc. IL-2, INF-g, and others) which cause pathologic effects.
How do some toxins inhibit protein synthesis?
These toxins irreversibly inhibit protein synthesis and cause the death of their host cells. Diphtheria toxin and Pseudo aeruginosa exotoxin A inactivate EF-2 (required for peptide chain elongation) by attaching an ADP-ribose to a modified histidine residue on EF-2. Shiga toxin (Shigella dysenteriae, E. coli, & ricin) are RNA N-glycosidases that remove a particular adenine residue from the 28s subunit and inactivate the ribosome.
What are some toxins that modify intracellular signaling pathways?
While these toxins alter specific cellular functions, they may or may not cause cell death. 1) Enterotoxins of Vibrio cholerea and E. coli. 2) Pertussis toxin 3) Enterotoxin I of E. coli 4) Anthrax edema factor (EF) Bacillus anthracis and Adenylate cyclase toxin Bordetella pertussis (both require activation by calmodulin and calcium inside the host cell) 5) Anthrax lethal factor (LF) 6) Clostridium difficile toxins A & B
What are some toxins that inhibit the release of neurotransmitters?
Botulinum (7 types) and tetanus (1 type) toxin. Both are zinc-dependent endopeptidases that inactivate specific SNARE proteins required for neuroexocytosis. Each toxin cleaves one specific protein at one specific site. Botulinum toxin inhibits the release at myoneural junctions, causing flaccid paralysis. Tetanus toxin inhibits the release from inhibitory interneurons in the spinal cord, causing sustained muscle contraction.
What are the common themes and pathways for toxins to enter cells?
Toxins with intracellular targets must cross the plasma membrane before they can exert their toxic effects. They usually are bi-functional proteins with separate domains or subunits designated A (active) and B (binding). Susceptibility or resistance to toxins is often determined by presence or absence of receptors on the target cells. They typically use normal membrane constituents as receptors. They usually enter target cells by endocytosis and enter the cytosol through forming pores in the endosome or through the ER via the retrograde pathway.
