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 Fe 2+ 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 Fe 2+ 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.

Genetic characterization of diphtheria tox B to evaluate vaccine efficacy in Indonesia

“…Tox PO is a segment of DNA located on the upstream of the genes that regulate expression of diphtheria toxins. Consensus -35 region Tox PO is similar to the location of Σ70 E. coli which starts at position 74 of the structural toxin gene and there are 2 possible tox promoter with consensus-10 region starting at position-54 and-48 from tox gene structural (2,19,20). Variances of bacterial virulence that have been reported are mutations in the toxin promoter-operator region (tox PO) that affect toxin expression (19).…”

“…Corynebacterium diphtheriae is a gram-positive, aerobic, pleomorphic coccobacillus that can produce a toxin by lysogenization with a corynebacteriophage carrying the tox gene, which can increase the severity of infection ( 1 , 2 ). The diphtheria toxin is a single-chain polypeptide with a molecular weight of about 58.36 kDa and 353 amino acids ( 3 ).…”

Isolation and Molecular Characterization of a Novel Podo-virus BIS08P22 having a Unique Terminase Enzyme Representing a new Genus in Class <em>Caudoviricetes</em>

“…Temperate phages have been a subject of interest since long with the discovery of two major virulence factors encoded by phages. One corynephages that carry tox gene producing Diphtheria toxin for Corynebacterium Diphtheriae [8] and C1 phage that produce Botulin toxin (C and D type) for Clostridium botulinum [9]. With advancement in genome studies and analysis of pathogenic bacteria, temperate phages are now known to carry a wide array of virulence factors such as toxins (tox, stx1, stx2, ctxAB etc.)…”

Endemic erythromycin resistant Corynebacterium diphtheriae in Vietnam in the 1990s

“…The toxin is encoded by the tox gene and is carried on a beta-corynephage [1,15]. Tox is regulated by the metallo-regulatory transcriptional regulator DtxR, which is repressor of tox, and is active when iron is not limited [16]. When secreted, the diphtheria exotoxin induces local tissue destruction and facilitates the formation of the pseudomembrane [1,15].…”