Phage Conversion and the Role of Bacteriophage and Host Functions in Regulation of Diphtheria Toxin Production by Corynebacterium diphtheriae

Abstract

Corynebacterium diphtheriae is the etiologic agent of diphtheria. Toxinogenic isolates of C. diphtheriae produce diphtheria toxin, a protein that inhibits protein synthesis in susceptible eukaryotic cells, whereas nontoxinogenic isolates of C. diphtheriae do not produce diphtheria toxin. The characteristic local and systemic manifestations of diphtheria are caused by diphtheria toxin. The toxinogenic phenotype of C. diphtheriae is determined by temperate corynephages whose genomes carry the tox gene that encodes diphtheria toxin. Toxinogenesis in C. diphtheriae is a paradigm for phage conversion, defined as a change in the phenotype of a bacterial host resulting from infection by a bacteriophage. In C. diphtheriae, transcription of the phage gene tox is negatively regulated by the diphtheria toxin repressor (DtxR), a corynebacterial metalloregulatory protein that requires intracellular Fe2+ as a cofactor under physiological conditions. This repressor is the master global regulator of iron-dependent gene expression in C. diphtheriae, and it controls intracellular iron homeostasis in C. diphtheriae by repressing under high-iron growth conditions and derepressing under low-iron growth conditions the transcription of genes that are essential for function of its multiple iron-acquisition systems. Production of diphtheria toxin by C. diphtheriae, therefore, reflects complex interactions between the tox operon on a corynephage, the bacterial regulatory protein DtxR, and the intracellular Fe2+ level which controls activity of DtxR and is, in turn, determined both by bioavailability of iron in the extracellular environment and activity of multiple DtxR-regulated systems that contribute to iron assimilation by C. diphtheriae.