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© Kenneth Todar, PhD

Toxigenicity

Two factors have great influence on the ability of Corynebacterium diphtheriae to produce the diphtheria toxin: (1) low extracellular concentrations of iron and (2) the presence of a lysogenic prophage in the bacterial chromosome. The gene for toxin production occurs on the chromosome of the prophage, but a bacterial repressor protein controls the expression of this gene. The repressor is activated by iron, and it is in this way that iron influences toxin production. High yields of toxin are synthesized only by lysogenic bacteria under conditions of iron deficiency.

The role of iron. In artificial culture the most important factor controlling yield of the toxin is the concentration of inorganic iron (Fe++ or Fe+++) present in the culture medium. Toxin is synthesized in high yield only after the exogenous supply of iron has become exhausted (This has practical importance for the industrial production of toxin to make toxoid. Under the appropriate conditions of iron starvation, C. diphtheriae will synthesize diphtheria toxin as 5% of its total protein). Presumably, this phenomenon takes place in vivo as well. The bacterium may not produce maximal amounts of toxin until the iron supply in tissues of the upper respiratory tract has become depleted. It is the regulation of toxin production in the bacterium that is partially controlled by iron. The tox gene is regulated by a mechanism of negative control wherein a repressor molecule, product of the DtxR gene, is activated by iron. The active repressor binds to the tox gene operator and prevents transcription. When iron is removed from the repressor (under growth conditions of iron limitation), derepression occurs, the repressor is inactivated and transcription of the tox genes can occur. Iron is referred to as a corepressor since it is required for repression of the toxin gene.

The role of B-phage. Only those strains of Corynebacterium diphtheriae that are lysogenized by a specific Beta phage produce diphtheria toxin. A phage lytic cycle is not necessary for toxin production or release. The phage contains the structural gene for the toxin molecule. The original proof rested in the demonstration that lysogeny of C. diphtheriae by various mutated Beta phages leads to production of nontoxic but antigenically-related material (called CRM for "cross-reacting material"). CRMs have shorter chain length than the diphtheria toxin molecule but cross react with diphtheria antitoxins due to their antigenic similarities to the toxin. The properties of CRMs established beyond a doubt that the tox genes resided on the phage chromosome rather than the bacterial chromosome.

Even though the tox gene is not part of the bacterial chromosome, the regulation of toxin production is under bacterial control since the DtxR (regulatory) gene is on the bacterial chromosome and toxin production depends upon bacterial iron metabolism.

Figure 5. The Beta phage that encodes the tox gene for the diphtheria toxin.

It is of some interest to speculate on the role of the diphtheria toxin in the natural history of the bacterium. Of what value should it be to an organism to synthesize up to 5% of its total protein as a toxin that specifically inhibits protein synthesis in eucaryotes and archaea? Possibly the toxin assists colonization of the throat (or skin) by killing epithelial cells or neutrophils. There is no evidence to suggest a key role of the toxin in the life cycle of the organism. Since mass immunization against diphtheria has been practiced, the disease has virtually disappeared, and C. diphtheriae is no longer a component of the normal flora of the human throat and pharynx. It may be that the toxin played a key role in the colonization of the throat in nonimmune individuals and, as a consequence of exhaustive immunization, toxigenic strains have become virtually...
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