Cytolethal distending toxin

The first recorded observation of a cytolethal-distending toxin was in 1987 in a pathogenic strain in E. coli isolated from a young patient.^[3] Later that year, scientists W.M. Johnson and H. Lior published the journal article "Production of Shiga toxin and a cytolethal distending toxin (CLDT) by serogroups of Shigella spp." in Microbiology Letters.^[1] The discovery of other bacteria producing CDT toxins continues to this day.

In 1994 Scott and Kaper cloned and sequenced a cdt operon from another E. coli strain, publishing in Infection and Immunity.^[1][5] The three genes discovered were denoted cdtA, cdtB, and cdtC.^[5]

In 1997, the first paper of many to show G2/M cell cycle arrest caused by a cytolethal distending toxin was published in Molecular Microbiology.^[1] The study focused on another E. coli strain. This paper was followed by a 1999 publication in Infectious Immunity, which demonstrated that Haemophilus ducreyi CDT causes cell death via apoptosis. This finding was also confirmed for other cytolethal distending toxins in subsequent studies.

The discovery of the homology of cdtB to mammalian DNase I and the current AB model for the toxin were published in early 2000. ^[2][6] Further research and the publication of crystal structures for the CDT toxins from two different species continues to support this model.^[1]

All known cytolethal distending toxins are produced by gram-negative bacteria in the Gammaproteobacteria and Campylobacterota. In several cases, the bacteria producing CDT are human pathogens. Medically important CDT producers include:^[1]

• Haemophilus ducreyi (chancroids)
• Aggregatibacter actinomycetemcomitans (periodontitis)
• Escherichia coli (various diseases)
• Shigella dysenteriae (dysentery)
• Salmonella enterica serotype Typhi (typhoid fever)
• Campylobacter upsaliensis (enterocolitis)
• Campylobacter jejuni (enterocolitis)

CDT-producing bacteria are often associated with mucosal linings, such as those in the stomach and intestines, and with persistent infections. The toxins are either secreted freely or associated with the membrane of the producing bacteria.^[1]

Individual cytolethal distending toxins are named for the bacterial species that they are isolated from. As of 2011, most scientists have adopted the practice of placing the first letter of both the genus and species in front of the toxin name to reflect its source (i.e., the CDT from Haemaphilus ducreyi is referred to as HdCDT).^[1][7] If several subspecies produce different toxins, as in the case of E. coli, Roman numerals may be added after the second letter.^[7] Both complete toxins and individual subunits are labeled using this convention.

In response to the continued discovery of additional cytolethal distending toxins, a 2011 review has proposed that the toxin names be expanded to include the first three letters of the species (i.e., HducCDT for Haemaphilus ducreyi CDT).^[1]

CDT toxins are genotoxins capable of directly damaging DNA in target cells. They are the only AB-type toxins discovered that display DNase activity, allowing them to introduce breaks into the target cell's DNA.^[1][4]

In many cell lines including human fibroblasts, epithelial cells, endothelial cells, and keratinocytes, CDTs cause G2/M cell cycle arrest, cytoplasmic distension, and eventual cell death via apoptosis.^[1][3][8] Most publications attribute the G2/M cycle arrest to the buildup of irreversible DNA damage from the toxin's DNase activity as the trigger for the G2/M cell cycle arrest, but other research suggests that this model is incomplete.^[8] The cytoplasmic distension is a direct result of the G2/M cell cycle arrest. The cell enlarges in preparation for mitosis, but cannot divide to restore its normal size. Aside from classical apoptosis, signs of cellular senescence has also been observed in normal and cancer cell lines (fibroblasts, HeLa and U2-OS) after CDT intoxication^[9]

In lymphocytes, cell death occurs quickly and is not preceded by significant cytoplasmic distension.^[8] The ability of these toxins to affect lymphocytes differently may be advantageous to the bacteria that utilize these toxins, but the mechanism behind this phenomenon is not yet well understood.

The active, assembled toxin is a tripartite structure with three distinct subunits- CdtA, CdtB, and CdtC. In terms of function, it is an AB toxin. In this context, the CdtB subunit is actually the catalytically active "A" subunit, and the CdtA and CdtC together form the binding "B" subunit, which helps the toxin bind and enter target cells.^[6] Some literature refers to the toxin structure as AB₂ to reflect the presence of both CdtA and CdtC.

Different from all other CDTs, Salmonella enterica serovar Typhi CDT (SeCDT) has no CdtA and CdtC homologues. However, encoded closely to the active subunit cdtb, the Pertussis-like toxin A and B (pltA/pltB) have been shown to be essential for cellular intoxication.^[10] PltA and PltB have a different structure from CdtA and CdtC, thus promoting CdtB activity in a different way. Both PltA and PltB have been found to bind directly to CdtB in vitro.^[10] In addition, different from all other CDTs, Salmonella genotoxin is produced only upon bacterial internalization in infected cells, thus the SeCDT traffic may differ remarkably from the canonical ones.