Figure 2.

Intoxication pathways of cholera toxin (CT), heat-labile toxin (LT), Shiga toxin (Stx) and C. difficile toxins A and B (TcdA/TcdB). (A). TcdA/TcdB cytotoxicity pathways. After internalization through endocytosis, toxins reach acidified endosomes. Low pH induces structural conformations in the toxin delivery domain leading to pore formation and translocation of glucosyltransferase domain (GTD) into the host cytosol. Rho family proteins become inactivated when GTD transfers a glucose unit from uridine diphosphate (UDP)-glucose to the switch I region of GTPase, leading to pathogenic effects or cell death. (B) CT and LT cytotoxicity pathways. After endocytosis and travelling of CT and LT as holotoxins through the trans Golgi network (TGN) and the ER, their catalytic A1 subunit is cleaved and released inside the cytoplasm. Thereafter, the A1 fragment ADP-ribosylate the Gsα subunit of G-protein and consequently activates adenylyl cyclase (AC). Activation of AC leads to elevated levels of cyclic AMP (cAMP) that activate protein kinase A (PKA). PKA stimulates the secretion of Cl⁻ through cystic fibrosis transmembrane regulator (CFTR) but provokes the inhibition of Na⁺ absorption leading to the disturbance of cellular ionic balance, and ultimately apoptosis. (C) STa cytotoxicity pathway. STa binds to guanylate cyclase C (GC-C) receptor and activates its intracellular catalytic domain, which induces cyclic GMP (cGMP). Elevated levels of cGMP activate cAMP-dependent PKA and inhibit phosphodiesterase 3 (PDE3). Subsequently, activated cAMP-dependent PKA along with PKGII, phosphorylate and open cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel. Through CFTR, Cl⁻ and HCO₃⁻ are released in the intestinal lumen, while Na⁺ reabsorption is inhibited as PKA has the ability to block the NHE3 channel. These modulating effects on the ionic channels induced by STa, finally result in an electrolyte imbalance that causes cell death. (D) Stx cytotoxicity pathway. Stx is internalized inside host cells (endocytosis) within early endosomes. Afterwards, Stx is following a retrograde transportation pathway, which is directed towards the transGolgi network (TGN) and subsequently reaches the endoplasmic reticulum (ER). In the ER, the enzymatically active A1 fragment translocates into the cytoplasm. Thereafter, it cleaves one adenine residue from the 28S RNA of the ribosomal subunit and thus inhibits protein synthesis leading to cell death. Created with biorender.com (accessed on 20 November 2020).