The Cytolethal Distending Toxin Contributes to Microbial Virulence and Disease Pathogenesis by Acting As a Tri-Perditious Toxin

Abstract

This review summarizes the current status and recent advances in our understanding of the role that the cytolethal distending toxin (Cdt) plays as a virulence factor in promoting disease by toxin-producing pathogens. A major focus of this review is on the relationship between structure and function of the individual subunits that comprise the AB2 Cdt holotoxin. In particular, we concentrate on the molecular mechanisms that characterize this toxin and which account for the ability of Cdt to intoxicate multiple cell types by utilizing a ubiquitous binding partner on the cell membrane. Furthermore, we propose a paradigm shift for the molecular mode of action by which the active Cdt subunit, CdtB, is able to block a key signaling cascade and thereby lead to outcomes based upon programming and the role of the phosphatidylinositol 3-kinase (PI-3K) in a variety of cells. Based upon the collective Cdt literature, we now propose that Cdt is a unique and potent virulence factor capable of acting as a tri-perditious toxin that impairs host defenses by: (1) disrupting epithelial barriers; (2) suppressing acquired immunity; (3) promoting pro-inflammatory responses. Thus, Cdt plays a key role in facilitating the early stages of infection and the later stages of disease progression by contributing to persistence and impairing host elimination.

The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines

“…CdtB is a dual-function enzyme that can also act as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase, perturbing PI-3K/Akt signaling (Shenker et al, 2014; Scuron et al, 2016). Phosphorylation of Akt (Ser473) and GSK-3β (Ser9) was evaluated with antibodies suitable for immunohistochemistry.…”

Virulence Traits of Inpatient Campylobacter jejuni Isolates, and a Transcriptomic Approach to Identify Potential Genes Maintaining Intracellular Survival

“…Semi-confluent cell monolayers were prepared (3 × 10 5 cells per well) in RPMI 1640 medium (BioWhittaker, Lonza, Basel, Switzerland) supplemented with 10% heat-inactivated calf bovine serum (Sigma-Aldrich), 10,000 U/mL penicillin, 10 µg/mL streptomycin, and 0.5 mg/mL neomycin, incubated overnight at 37 • C in a humidified incubator with 5% CO 2 . The next day the bacterial suspensions with various optical densities (OD 600nm = 0.01, 0.1, and 1.0) were added to reach a multiplicity of infection (MOI) ranging from 10 to 500 [45]. Plates were centrifuged at 100× g for 10 min at room temperature and incubated at 37 • C with 5% CO 2 for 3 h. For the adhesion and invasion assay, separate parallel plates were used.…”

The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis

“…The cytolethal distending toxin (Cdt) is a putative virulence factor that is produced by a wide range of human pathogens capable of colonizing mucocutaneous tissue, resulting in disease characterized by persistent infection and inflammation (reviewed in References [1,2]). In general, Cdts are heterotrimeric complexes encoded by an operon of three genes designated cdtA, cdtB, and cdtC which encode three polypeptides: CdtA, CdtB, and CdtC with molecular masses of [23][24][25][26][27][28][29][30][28][29][30][31][32], and 19-20 kDa, respectively [3][4][5][6][7][8][9][10][11][12][13].…”