Microbial toxins Flashcards
Microbial toxins definition
Microbial toxins are macromolecular products of microbes
that cause harm to susceptible animals by altering cellular structure or function. They are very potent, and the clostridial neurotoxins (botulinum and tetanus toxins) are the most toxic biological substances known.
Importance:
1) Some toxins cause the major manifestations of specific diseases
2) other toxins contribute to pathogenesis without causing unique signs or symptosm
3) Toxin-mediated diseases cause significant morbidity and mortality
Traditional methods to show that a specific toxin has a role in pathogenesis
1) Show that purified toxin causes the same symptoms or signs as infection by the
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
toxin-producing microbe.
the microbe regains the ability to produce toxin.
Molecular version of koch’s postulates
1) Show that the phenotype or property to be investigated (e.g., 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 putative 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.
Structure and function of microbial toxins: Composition and properties
1) Bacterial protein toxins are usually heat-labile, immunogenic, and neutralized by specific antibodies. Originally called ‘exotoxins’ Some are secreted into the culture medium. Others are released by lysis of bacteria.
2) Lipopolysaccharides of gram neg bacteria were first called “endotoxin”. LPS is a PAMP recognized by eh innate immune system and elicits host responses by LPS binding protein CD14, TLR4, and other molecules.
LPS response
Low LPS doses activate macrophages, B-cells and the alternative complement pathway to cause fever, production of acute phase reactants, polyclonal antibody synthesis, and inflammation. High doses of LPS cause shock and disseminated intravascular coagulation. Many of the biologic effects of LPS are mediated by cytokines
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #1
1) Toxins that facilitate spread of microbes through tissues. Some toxic enzymes break down extracellular matrix or degrade debris in necrotic tissue (e.g., hyaluronidase, collagenase, elastase, deoxyribonuclease, and streptokinase), thereby enhancing spread of microbes.
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #2
2) Toxins that damage cellular membranes. Most membrane-damaging toxins kill target cells. Many are called hemolysins, because it is easy to detect their action on erythrocytes. Usually these toxins also damage other cells and are more accurately called cytolysins. Many membrane-damaging toxins insert into membranes and assemble into multimeric complexes that form pores, thereby causing lysis of target cells. Others, such as lecithinases, degrade specific cell membrane components and disrupt the integrity of the membranes.
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #3
Toxins that stimulate cytokine production. The pyrogenic exotoxins include erythrogenic (scarlatinal) toxins of Streptococcus pyogenes and the enterotoxins and toxic shock syndrome toxin (TSST-1) of Staphylococcus aureus. They are involved in scarlet fever, food poisoning, and toxic shock syndrome. The pyrogenic exotoxins belong to a larger class of molecules known as superantigens. The superantigens are the most potent known T cell activators. They act by binding both to major histocompatibility (MHC) class II molecules on antigen-presenting cells and to specific Vβ  chains on T cells at a site that is different from the antigen-binding site, and they activate much larger numbers of T cells than any specific antigen does. Superantigens stimulate excessive production of cytokines (including interleukin-2, interferon gamma, and others), thereby causing pathologic effects.
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #4
Toxins that inhibit protein synthesis. These toxins inhibit protein synthesis irreversibly and cause death of intoxicated host cells.
a) Diphtheria toxin and Pseudomonas aeruginosa exotoxin A inactivate elongation factor 2 (EF-2), which is required for peptide chain elongation. They are both ADP ribosyltransferases that transfer adenosine diphosphate ribose (ADP-ribose) from nicotinamide adenine dinucleotide (NAD) to a modified histidine residue called diphthamide on EF-2, thereby inactivating EF-2 in the cytoplasm.
b) Shiga toxins of Shigella dysenteriae and E. coli, and the plant
toxin ricin, are highly specific RNA N-glycosidases that remove one particular adenine residue from the 28S RNA of the 60S ribosomal subunit, thereby inactivating the ribosomes.
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #5
Toxins that modify intracellular signaling pathways. These toxins alter specific cellular functions and may or may not cause cell death. : 1) Heat-labile enterotoxins of Vibrio cholerae and Escherichia
coli
2) Pertussis toxin
3) Heat-stable enterotoxin I (ST-I) of E.coli
4) Anthrax edema factor (EF) and adenylate cyclase toxin. (requires activation by calmodulin and calcium)
5) Anthrax lethal factor (LF)
6) C.Diff toxins A and B.
Structure and function of microbial toxins: classifying bacterial protein toxins based on their mechanisms of action: #6
Toxins that inhibit release of neurotransmitter. 1) Botulinum toxin
2) Tetanus toxin
3) Tetanus toxin and the botulinum toxins are zinc-dependent endopeptidases. Tetanus toxin and the botulinum toxins are zinc-dependent endopeptidases
4) Botulinum toxin is used therapeutically to treat several focal dystonias and involuntary movement disorders.
Mechanisms and Pathways for Entry of Toxins into Cells.
1) Toxins that act extracellularly or on plasma membranes are diverse
in structure and function. Their specificity is usually determined directly by the target of their action.
2) Toxins with intracellular targets must cross the plasma membrane before they can exert their toxic effects.
common features of intracellular target toxins
1) They usually are bi-functional proteins with separate domains or subunits designated A (for active) and B (for binding). Susceptibility or resistance to toxins is often determined by presence or absence of receptors on the target cells.
2) They typically use normal membrane constituents as receptors
3) They usually enter target cells by endocytosis - the active portion of the toxin is translocated to the cytosol to interact with its target.
Principles of prophylaxis and treatment of toxin-mediated diseases: #1
antitoxic antibodies (antitoxins) bind to toxins and prevent their toxicity (neutralization). Antitoxins usually do not prevent infection by the toxin-producing bacteria or reverse toxic effects after the toxin has entered host cells.
