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.

Keywords: PI-3 kinase; epithelial cells; inflammation; lymphocytes; macrophages; toxin; virulence.

Figure 1

Overview of Cdt's role as a virulence factor. Most Cdts are heterotrimeric AB₂ toxins that are capable of affecting multiple cell types due to the ability of the binding (B) subunits to bind to cells via a common membrane moiety, cholesterol. Furthermore, the active (A) subunit, CdtB, functions as a PIP3 phosphatase and is therefore capable of inducing a blockade of a universally employed signaling cascade, PI-3K. We now propose that in its capacity as a virulence factor, Cdt functions as a tri-perditious toxin that is capable of impairing host defense in three ways: (1) induce cell cycle arrest and apoptosis in epithelial cells thereby altering epithelial barriers and facilitating infection by Cdt-producing pathogens; (2) induce cell cycle arrest and apoptosis in lymphocytes thereby impairing acquired immunity and promoting persistent infection; and (3) altering macrophage function leading to a pro-inflammatory response as a result of increased cytokine synthesis and inflammasome activation. Please note that we have not excluded the possibility that some Cdts and/or some cells may under some conditions be intoxicated as a result of CdtB associated DNase activity.

Figure 2

Structural similarity between the active sites of CdtB and IP5P. The superposition was based on conserved residues in the active sites of CdtB [blue; PDB code 2f2f_B (Yamada et al., 2006)] and IP5P [red; PDB code 1i9z_A (Tsujishita et al., 2001)]. The two sets of 6 conserved residues are aligned well, with an RMSD of 0.26 Å. Residue numbers correspond to CdtB structure. Parts of superimposed structures were clipped out of viewing plane for clarity.