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. 2021 Apr 28;6(2):64. doi: 10.3390/tropicalmed6020064

Figure 1.

Figure 1

Pathogenesis of cholera and mode of action of the cholera toxin. (A) In the 1970s, the pathogenesis of cholera rapidly became better understood than any other infectious disease, as summarized in this figure from a Nobel Symposium on cholera in 1978 (A-M. Svennerholm, p.162 in [4]). After ingesting contaminated food or water, V. cholerae bacteria colonize the small intestine and secrete the cholera toxin, a doughnut-like protein with a central enzymatic toxic-active A (A1 + A2) subunit that is associated with a cell-binding pentamer of B subunits (B5). After binding to cell surface receptors identified as the GM1 ganglioside (the first-ever structurally defined mammalian cell receptors), the A subunit dissociates from the B subunits and its A1 entity binds to and ADP-ribosylates the GTP-binding Gs adenyl cyclase protein. This leads to the production of cyclic AMP (cAMP), which in turn induces the secretion of chloride, bicarbonate, and water from intestinal crypt cells and blocks sodium chloride and water uptake from villus cells, resulting in the watery diarrhea, dehydration, and acidosis that is typical of severe cholera. (B) Subsequent crystallographic studies have confirmed the A:B5 dough-nut structure of the cholera toxin and further detailed knowledge has been gained about the way the cholera toxin induces fluid secretion. After binding to GM1 ganglioside receptors, which are mainly localized in lipid rafts on the cell surface, the toxin is endocytosed and, via a retrograde pathway, travels to the endoplasmic reticulum (ER). In the ER, the A subunit dissociates from the B subunits and, through translocation via the ER degradosome pathway, A1 is released into the cytosol. After refolding, A1 ADP-ribosylates Gs, stimulating the adenyl cyclase (AC) complex to produce increased levels of cAMP, leading to the activation of protein kinase A (PKA), phosphorylation of the major chloride channel CFTR (the cystic fibrosis transmembrane conductance regulator), and the secretion of chloride (Cl−), among other effects, resulting in the often lethal cholera diarrhea and fluid loss.