Microbial Toxins Flashcards
Define and describe microbial toxins:
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 of microbial toxins:
1) Some toxins cause the major manifestations of specific diseases (for example: in botulism, cholera, diphtheria, whooping cough, scalded skin syndrome, scarlet fever, tetanus, or toxic shock syndrome).
2) Other toxins contribute to pathogenesis without causing unique signs or symptoms (for example, pneumolysin).
3) Toxin-mediated diseases cause significant morbidity and mortality, particularly in developing countries.
Explain how a microbial toxin is implicated in pathogenesis of an infectious disease
1) Bacterial protein toxins are usually heat-labile, immunogenic, and neutralized by specific antibodies. They were originally called “exotoxins” to indicate that they were found outside the bacterial cells
2) Lipopolysaccharides (LPS) of gram negative bacteria were first called “endotoxin” to indicate their association with bacterial cells. . 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.
Explain the mechanisms of action of the microbial toxins described here: 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
Explain the mechanisms of action of the microbial toxins described here: 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.
Explain the mechanisms of action of the microbial toxins described here: 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. Superantigens stimulate excessive production of cytokines (including interleukin-2, interferon gamma, and others), thereby causing pathologic effects
Explain the mechanisms of action of the microbial toxins described here: 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 to 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.
Explain the mechanisms of action of the microbial toxins described here: Toxins that modify intracellular signaling pathways.
These toxins alter specific cellular functions and may or may not cause cell death.
a) Heat-labile enterotoxins of Vibrio cholerae and Escherichia coli are ADP ribosyltransferases
b) Pertussis toxin is an ADP ribosyltransferase
c) Heat-stable enterotoxin I (ST-I) of E. coli activates cell membrane-associated guanylate cyclase
d) Anthrax edema factor (EF) from Bacillus anthracis and adenylate cyclase toxin from Bordetella pertussis are adenylate cyclases
e) Anthrax lethal factor (LF) is an endopeptidase
f) Clostridium difficile toxins A and B are glucosyl transferases
Explain the mechanisms of action of the microbial toxins described here: Toxins that inhibit release of neurotransmitters
a) Botulinum toxin (7 antigenic types, A-G) causes flaccid paralysis of skeletal muscles
b) Tetanus toxin (1 antigenic type) causes sustained muscular contraction (spastic paralysis/tetany) of skeletal muscles
c) Tetanus toxin and the botulinum toxins are zinc-dependent endopeptidases
d) Botulinum toxin is used therapeutically to treat several focal dystonias and involuntary movement disorders
What do antitoxic antibodies (antitoxins) do?
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.
What are toxoids?
Derivatives of toxins that retain immunogenicity but lack toxicity. They are used as vaccines for long term protection against toxin-mediated diseases.
Passive immunization is
the administration of antibodies to a patient to provide immediate but temporary protection against a toxin or infectious agent. The duration of immunity is limited by degradation of the antibodies in the patient.
Active immunization involves
administration of toxoid to a patient in order to elicit production of specific anti-toxic antibodies.
1) A primary series of immunizations and periodic booster doses are required to achieve and maintain protective levels of antitoxin.
2) Active immunity can persist for many years because of immunologic memory.
Explain the principles for developing novel therapeutic agents based on toxins
“Immunotoxins” (and “hormonotoxins”) are hybrid molecules consisting of a toxin fragment that lacks the receptor-binding domain of the native toxin (derived, for example, from diphtheria toxin, exotoxin A, or ricin) and that is linked (by chemical conjugation or as recombinant fusion protein) to a ligand (such as a monoclonal antibody or a “single-chain” antibody [in the case of an immunotoxin] or a hormone or its receptor-binding domain [in the case of an hormonotoxin]) that exhibits binding specificity for a specific receptor than is different from the receptor for the native toxin. The rationale is enable the immunotoxin or hormonotoxin to bind to cells that express that alternative receptor and intoxicate them by delivering the toxic fragment of the native toxin.
Many immunotoxins are designed to kill tumor cells that display a tumor-specific receptor but not to kill normal cells that lack that receptor. Immunotoxins are being tested as potentially valuable therapeutic agents for treatment of specific cancers, autoimmune diseases, and other disorders.
