Corynebacterium diphtheriae: iron-mediated activation of DtxR and regulation of diphtheria toxin expression.

A detailed understanding of the molecular biology and genetics of both the regulation of diphtheria toxin expression and the structure-function relationships and mode of action of the toxin is known. The existence of virulence determinants in C. diphtheriae beyond those associated with diphtheria toxin is demonstrated by the recently reported outbreak of invasive disease caused by a clonal focus of nontoxigenic C. diphtheriae among intravenous drug users in Switzerland. The regulation of expression of the tox gene, as well as the genes involved in iron acquisition and utilization, is under the control of the C. diphtheriae-encoded iron-activated repressor diphtheria toxin repressor (DtxR). The protein-protein interactions stabilizing DtxR dimers arise mostly from hydrophobic associations. The X-ray structure of the C-terminal domain of DtxR shows that this region of the repressor is composed of five antiparallel β-sheets and two short α-helices. Diphtheria toxin is the primary virulence factor expressed by toxigenic strains of C. diphtheriae. The structural gene encoding diphtheria toxin is carried by a family of closely related corynebacteriophages, the best studied of which is corynephage. The C. diphtheriae genome sequence has also permitted examination of microbial speciation and evolution. Outbreaks of clinical diphtheria almost always occur in individuals who have not become immunized and who have been exposed to a carrier. Molecular epidemiologic analysis of toxigenic strains of C. diphtheriae isolated from this epidemic has provided further insight into the virulence of this pathogen.