Molecular Mechanisms Of Cycle Arrest And Apoptosis In Lymphoid Cells Elicited By Cytolethal Distending Toxin, A Genotoxin Produced By Campylobacter Jejuni And Helicobacter Hepaticus

Cytolethal distending toxin (CDT) is a heterotrimeric AB type genotoxin produced by several clinically important Gram negative mucocutaneous bacterial pathogens. Irrespective of the bacterial species of origin, CDT causes characteristic and irreversible cell cycle arrest and apoptosis in a broad range of cultured mammalian cell lineages. The active subunit CdtB has structural homology with phosphodiesterase family of enzymes including mammalian deoxyribonuclease I, and alone is necessary and sufficient to account for cellular toxicity. Indeed, mammalian cells treated with CDT initiate a DNA damage response similar to that elicited by ionizing radiation-induced DNA double strand breaks resulting in cell cycle arrest and apoptosis. The mechanism of CDT-induced apoptosis remains incompletely understood, but appears to involve both p53-dependent and -independent pathways. While epithelial, endothelial and fibroblast cell lines respond to CDT by undergoing arrest of cell cycle progression resulting in nuclear and cytoplasmic distension that precedes apoptotic cell death, cells of hematopoietic origin display rapid apoptosis following a brief period of cell cycle arrest. In this review, the ecology and molecular biology of bacterial CDT and the molecular mechanisms of CDT-induced cytoxicity are critically appraised. Understanding the contribution of a broadlyconserved bacterial genotoxin that blocks progression of the cell cycle and causes cell death should assist with elucidating disease mechanisms for these important pathogens. This article has been published in Microbiology: 1 Jinadasa, R. N. , Bloom, S. E. , Weiss, R. S. & Duhamel, G. E. (2011). Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages. Microbiology 157, 1851-1875. Author contributions: R.N. J. performed the experiemnts. R.N. J, S.E. B, R.S. W and G.E. D wrote the paper. 2 Introduction Johnson and Lior’s seminal observations over two decades ago demonstrating a novel heatlabile toxin in culture filtrates obtained from certain Escherichia coli, Shigella dysenteriae, and Campylobacter jejuni which caused distinctive and progressive cytoplasmic and nuclear enlargement of cultured mammalian cells, so called cytolethal distending toxin (CDT) uncovered a novel paradigm amongst bacterial toxins and virulence mechanisms (Johnson & Lior, 1987; Johnson & Lior, 1988a; Johnson & Lior, 1988b). It was not until several years later that Scott and Kaper (1994) identified the genes encoding CDT in E. coli, which set the stage for fundamental investigations into the ecology, biochemistry, and molecular mechanisms of cellular toxicity associated with this novel bacterial toxin (Table 1.1). Few years later, Peres and coworkers (1997) noted for the first time that the cellular enlargement associated with CDT intoxication was attributable to cell cycle arrest (Peres et al., 1997). Soon after that, Gelfanova and coworkers (1999) demonstrated that the underlying mechanism of CDT-induced cell death involved apoptosis (Gelfanova et al., 1999).