Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins

Abstract

Research on the human gut pathogen Clostridium difficile and its toxins has gained much attention, particularly as a consequence of the increasing threat to human health presented by emerging hypervirulent strains. Toxin A (TcdA) and B (TcdB) are the two major virulence determinants of C. difficile. Both are single-chain proteins with a similar multidomain architecture. Certain hypervirulent C. difficile strains also produce a third toxin, namely binary toxin CDT (Clostridium difficile transferase). As C. difficile toxins are the causative agents of C. difficile-associated diseases (CDAD), such as antibiotics-associated diarrhea and pseudomembranous colitis, considerable efforts have been expended to unravel their molecular mode-of-action and the cellular mechanisms responsible for their uptake. Notably, a high proportion of studies on C. difficile toxins were performed in European laboratories. In this chapter we will highlight important recent advances in C. difficile toxins research.

A Drosophila Model for Clostridium difficile Toxin CDT Reveals Interactions with Multiple Effector Pathways

“…In humans, CDIs are the main cause of inflammatory diarrhea after antibiotic treatment, and previous studies in mammalian systems showed that C. difficile toxins induce depolymerization of F-actin, leading to deterioration of intestinal microvilli (Abt et al, 2016;Aktories et al, 2018;Just et al, 1995aJust et al, , 1995bJust et al, , 1995cPapatheodorou et al, 2018). Possible complications of CDI are pseudomembranous colitis (PMC), toxic megacolon, perforation of the colon, and sepsis (Martin et al, 2016).…”

“…CDI pathogenesis has been mostly attributed to two related toxins secreted by C. difficile: toxin A (TcdA) and toxin B (TcdB) (Bartlett, 2002;Just and Gerhard, 2004;Kelly and LaMont, 2008;Voth and Ballard, 2005). Both toxins glucosylate and irreversibly inactivate small GTPases of the Rho/Rac/Cdc42 family, leading to disruptions in F-actin networks, subsequent epithelial damage, and increased barrier permeability due to loss of tight junction integrity (Aktories et al, 2018;Just et al, 1995aJust et al, , 1995bPapatheodorou et al, 2018). In addition, 35% of C. difficile isolates express a third toxin, C. difficile transferase (CDT), known to confer hyper-virulence during infection (Geric et al, 2004;Goncalves et al, 2004;Stubbs et al, 2000), and belonging to a conserved family of binary effectors from various enteric pathogens such as C. botulinum (C2 toxin), C. perfringens (BEC), and B. cereus (VIP) (Stiles et al, 2014).…”

Novel Chimeric Protein Vaccines Against Clostridium difficile Infection

“…We included C-termial regions of TcdA (aa 1848–2710) and TcdB (aa 1851–2366) in two fusion proteins Tcd169 and Tcd169Fl. Historically, these regions are called combined repetitive oligopeptides (CROP), and were considered RBD for TcdA and TcdB ( 50 , 51 ). Recently, two binding sites were postulated within the newly defined RBD of TcdB.…”

Combined Pharmacological Inhibition of Cyclophilins, FK506-Binding Proteins, Hsp90, and Hsp70 Protects Cells From Clostridium botulinum C2 Toxin

“…C. difficile infections (CDI) are still on the rise in hospitals of Western countries and pose a severe threat due to life-threatening symptoms such as antibiotic-associated diarrhea or pseudomembranous colitis. CDT has been identified as a novel virulence factor produced by hypervirulent C. difficile strains and most likely contributes to an improved colonization of C. difficile in the human gut ( Aktories et al, 2018 ; Papatheodorou et al, 2018 ).…”