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Tag words: pathogenic bacteria, bacterial pathogenicity, invasiveness, toxigenesis, colonization, specific adherence, adhesin, receptor, invasion, invasin, coagulase, leucocidin, hemolysin, streptokinase, phagocytosis, phagosome, lysosome, phagolysosome, immunological tolerance, antigenic disguise, immunosuppression, antigenic variation, protein toxins, botulinum toxin, diphtheria toxin, anthrax toxin, tetanus toxin, pertussis toxin, cholera enterotoxin, adenylate cyclase, staph enterotoxin, TSST, pyrogenic exotoxin, superantigen, shiga toxin, E. coli LT toxin, ST toxin, endotoxin, lipopolysaccharide, LPS, Lipid A, O antigen, O polysaccharide, toxoid, pathogenicity island.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Mechanisms of Bacterial Pathogenicity (page 7)

(This chapter has 8 pages)

© Kenneth Todar, PhD

TOXIGENESIS

Two types of bacterial toxins

At a chemical level there are two types of bacterial toxins:

lipopolysaccharides, which are associated with the cell walls of Gram-negative bacteria.

proteins, which may be released into the extracellular environment of pathogenic bacteria.

The lipopolysaccharide (LPS) component of the Gram-negative bacterial outer membrane bears the name endotoxin because of its association with the cell wall of bacteria.

Most of the protein toxins are thought of as exotoxins, since they are "released" from the bacteria and act on host cells at a distance.

BACTERIAL PROTEIN TOXINS

The protein toxins are typically soluble proteins secreted by living bacteria during exponential growth. The production of protein toxins is generally specific to a particular bacterial species (e.g. only Clostridium tetani produces tetanus toxin; only Corynebacterium diphtheriae produces the diphtheria toxin). Usually, virulent strains of the bacterium produce the toxin (or range of toxins) while nonvirulent strains do not, such that the toxin is the major determinant of virulence. Both Gram-positive and Gram-negative bacteria produce soluble protein toxins. Bacterial protein toxins are the most potent poisons known and may show activity at very high dilutions.

The protein toxins resemble enzymes in a number of ways. Like enzymes, bacterial exotoxins:

are proteins

are denatured by heat, acid, proteolytic enzymes

have a high biological activity (most act catalytically)

exhibit specificity of action

As enzymes attack specific substrates, so bacterial protein toxins are highly specific in the substrate utilized and in their mode of action. The substrate (in the host) may be a component of tissue cells, organs, or body fluid. Usually the site of damage caused by the toxin indicates the location of the substrate for that toxin. Terms such as "enterotoxin", "neurotoxin", "leukocidin" or "hemolysin" are sometimes used to indicate the target site of some well-defined protein toxins.

Certain protein toxins have very specific cytotoxic activity (i.e., they attack specific cells, for example, tetanus or botulinum toxins), but some (as produced by staphylococci, streptococci, clostridia, etc.) have fairly broad cytotoxic activity and cause nonspecific death of tissues (necrosis). Toxins that are phospholipases may be relatively nonspecific in their cytotoxicity because they cleave phospholipids which are components of host cell membranes resulting in the death of the cell by leakage of cellular contents. This is also true of pore-forming "hemolysins" and "leukocidins".

A few protein toxins obviously bring about the death of the host and are known as "lethal toxins", and even though the tissues affected and the target sites may be known, the precise mechanism by which death occurs is not understood (e.g. anthrax toxin).

As "foreign" substances to the host, most of the protein toxins are strongly antigenic. In vivo, specific antibody (antitoxin) neutralizes the toxicity of these bacterial proteins. However, in vitro, specific antitoxin may not fully inhibit their enzymatic activity. This suggests that the antigenic determinant of the toxin is distinct from the active (enzymatic) portion of the protein molecule. The degree of neutralization of the enzymatic site may depend on the distance from the antigenic site on the molecule. However, since the toxin is fully neutralized in vivo, this suggests that other (host) factors must play a role.

Protein toxins are inherently unstable: in time they lose their toxic properties but retain their antigenic ones. This was first discovered by Ehrlich and he coined the term toxoid for this product. Toxoids are detoxified toxins which retain their antigenicity and their immunizing capacity. The formation of toxoids can be accelerated by treating toxins with a variety of reagents including formalin, iodine, pepsin, ascorbic acid, ketones, etc. The mixture is maintained at 37o at pH range 6 to 9 for several weeks. The resulting toxoids can be use for artificial immunization against diseases caused by pathogens where the primary determinant of bacterial virulence is toxin production. Toxoids are the immunizing agents against diphtheria and tetanus that are part of the DPT vaccine.

A + B Subunit Arrangement of Protein Toxins

Many protein toxins, notably those that act intracellularly (with regard to host cells), consist of two components: one component (subunit A) is responsible for the enzymatic activity of the toxin; the other component (subunit B) is concerned with binding to a specific receptor on the host cell membrane and transferring the enzyme across the membrane. The enzymatic component is not active until it is released from the native toxin. Isolated A subunits are enzymatically active and but lack binding and cell entry capability. Isolated B subunits may bind to target cells (and even block the binding of the native A+B toxin), but they are nontoxic. There are a variety of ways that toxin subunits may be synthesized and arranged: A-B or A-5B indicates that subunits synthesized separately and associated by noncovalent bonds; A/B denotes subunit domains of a single protein that may be separated by proteolytic cleavage; A + B indicates separate protein subunits that interact at the target cell surface; 5B indicates that the binding domain is composed of 5 identical subunits.

Tertiary structure of the pertussis toxin produced by Bordetella pertussis. Pertussis toxin is a member of the A-B bacterial toxin superfamily. It is a hexameric protein comprising five distinct subunits, designated S1-S5. S2, S3, S4 and S5 comprise the B oligomer, responsible for binding the toxin to the cell surface. Each subunit is translated separately with an amino-terminal signal sequence which is cleaved during transport to the periplasm. S2 and S3 function as adhesins, S2 binds specifically to a glycolipid called lactosylceramide, which is found primarily on the ciliated epithelial cells. S3 binds to a glycoprotein found mainly on phagocytic cells.

Attachment and Entry of Toxins

There are at least two mechanisms of toxin entry into target cells. In one mechanism called direct entry, the B subunit of the native toxin (A+B) binds to a specific receptor on the target cell and induces the formation of a pore in the membrane through which the A subunit is transferred into the cell cytoplasm. In an alternative mechanism, the native toxin binds to the target cell and the A+B structure is taken into the cell by the process of receptor-mediated endocytosis (RME). The toxin is internalized in the cell in a membrane-enclosed vesicle called an endosome. H+ ions enter the endosome lowering the internal pH which causes the A+B subunits to separate. Somehow, the B subunit affects the release of the A subunit from the endosome so that it will reach its target in the cell cytoplasm. The B subunit remains in the endosome and is recycled to the cell surface. In both cases, a large protein molecule must insert into and cross a membrane lipid bilayer. This activity is reflected in the ability of most A/B native toxins, or their B components, to insert into artificial lipid bilayers, creating ion permeable pathways.

Other Considerations

In keeping with the observation that genetic information for functions not involved in viability of bacteria is frequently located extrachromosomally, the genes encoding toxin production are generally located on plasmids or in lysogenic bacteriophages. Thus the processes of genetic exchange in bacteria, notably conjugation and transduction, can mobilize these genetic elements between strains of bacteria, and therefore may play a role in determining the pathogenic potential of a bacterium.

Why certain bacteria produce such potent toxins is mysterious and is analogous to asking why an organism should produce an antibiotic. The production of a toxin may play a role in adapting a bacterium to a particular niche, but it is not essential to the viability of the organism. Many toxigenic bacteria are free-living in Nature and in associations with humans in a form which is phenotypically identical to the toxigenic strain but lacking the ability to produce the toxin.

There is conclusive evidence for the pathogenic role of diphtheria, tetanus and botulinum toxins, various enterotoxins, staphylococcal toxic shock syndrome toxin, and streptococcal erythrogenic toxin. And there is clear evidence for the pathological involvement of pertussis toxin, anthrax toxin, shiga toxin and the necrotizing toxins of clostridia in host-parasite relationships.
 
Table 4. SOURCES AND ACTIVITIES OF BACTERIAL TOXINS
NAME OF TOXIN BACTERIUM INVOLVED ACTIVITY
Anthrax toxin (EF) Bacillus anthracis Edema Factor (EF) is an adenylate cyclase that causes increased levels in intracellular cyclic AMP in phagocytes and formation of ion-permeable pores in membranes (hemolysis) 
Adenylate cyclase toxin Bordetella pertussis Acts locally to increase levels of cyclic AMP in phagocytes and formation of ion-permeable pores in membranes (hemolysis)
Cholera enterotoxin Vibrio cholerae ADP ribosylation of G proteins stimulates adenylate cyclase and increases cAMP in cells of the GI tract, causing secretion of water and electrolytes
E. coli LT toxin Escherichia coli Similar to cholera toxin
Shiga toxin Shigella dysenteriae Enzymatically cleaves rRNA resulting in inhibition of protein synthesis in susceptible cells
Botulinum toxin Clostridium botulinum Zn++ dependent protease that inhibits neurotransmission at neuromuscular synapses resulting in flaccid paralysis
Tetanus toxin Clostridium tetani Zn++ dependent protease that inhibits neurotransmission at inhibitory synapses resulting in spastic paralysis
Diphtheria toxin Corynebacterium diphtheriae ADP ribosylation of elongation factor 2 leads to inhibition of protein synthesis in target cells
Pertussis toxin Bordetella pertussis ADP ribosylation of G proteins blocks inhibition of adenylate cyclase in susceptible cells
Staphylococcus enterotoxins* Staphylococcus aureus Massive activation of the immune system, including lymphocytes and macrophages, leads to emesis (vomiting)
Toxic shock syndrome toxin (TSST-1)* Staphylococcus aureus Acts on the vascular system causing inflammation, fever and shock
Pyrogenic exotoxins (SPE) e.g. Erythrogenic toxin (scarlet fever toxin)* Streptococcus pyogenes Causes localized erythematous reactions
* The "pyrogenic exotoxins" produced by Staphylococcus aureus and Streptococcus pyogenes have been designated as superantigens. They represent a family of molecules with the ability to elicit massive activation of the immune system. These proteins share the ability to stimulate T cell proliferation by interaction with Class II MHC molecules on APCs and specific V beta chains of the T cell receptor. The important feature of this interaction is the resultant production of IL-1, TNF, and other lymphokines which appear to be the principal mediators of disease processes associated with these toxins.




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