Cholera toxin

From The School of Biomedical Sciences Wiki
Revision as of 09:58, 3 December 2018 by Nnjm2 (Talk | contribs)
Jump to: navigation, search



Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the bacterium Vibrio cholerae[1]. CT is the cause of cholera, often from dirty water. CT is transmitted between patients via the faecal-oral route, therefore, is often found in countries with poor sanitation. The cholera toxin affects the epithelial cells in the intestine by interfering with the cells signalling pathway, the toxin causes over activation of the signalling pathway that controls the activity of chloride channel proteins. The toxin activates the chloride channel proteins to open and allow the movement of chloride ions out of the cell in the absence of the signalling molecule. CT is characterised by its ability to cause severe diarrhoea, often leading to dehydration[2]. In extreme circumstances cholera can lead to death.

V. cholerae

V. cholerae is a comma-shaped, gram-negative bacterium and has one flagellum at the positioned at the pole of the cell. V. cholerae, known to lie dormant in water and food supplies that have been contaminated by human excrement is a concern for large-scale outbreaks[3]. Once V. cholerae enters its human host, the bacterium propels themselves through the mucous membranes of the ileum attaching themselves to the epithelial lining[4] releasing CT thus activating a cascade of cell signalling pathways leading to massive fluid loss from the ileum and duodenum[5]. V. cholerae secretes the enterotoxin CT in a very efficient manner with more than 90% of the toxin found extracellularly. CT, once secreted into a system, initiates its toxic action by means of binding to high-affinity cell membrane receptors identified to be the ganglioside or GM1 receptors[6].

Structure of the Toxin

CT is a member of the AB5 family of toxins and consists of subunits, Alpha and 5 Beta. ). The A subunit which is located at the centre of the toxin whilst the five beta subunits are arranged into a pentameric ring and are responsible for binding the toxin to a cell's membrane[7], weighing 11 kDa each and are made from a chain of 103 amino acids, binds to five ganglioside GM1 receptors on the plasma membrane and triggers endocytosis of the toxin, whilst the Alpha subunit is made up of an A1 and A2 chain, the alpha subunit is made up of a chain of 240 amino acids. A1 is enzymatic and does most of the work, once inside the cell. A2 is an extended alpha helix, connecting the alpha subunit to the Beta subunit. The alpha subunit is cleaved apart once inside the cell, allowing the A1 chain to dissociate and begin its catalytic activity, leaving the A2 domain which had been anchoring the A1 chain to the Beta subunit[8].

Mechanism of Infection

The location of CTX’s function is found in the lumen of the small intestine[9]., where, in an effort to infect cells, the bacterium V. cholerae produces an invasin[10]. The gastrointestinal (GI) tract is coated with a mucus lining with the aim to prevent pathogens such as CT from entering the endothelial cells of the gut lining[11][12].

Neuraminidase is produced by cholera cells as an invasion, neuraminidase is part of a group of enzymes responsible for removing the carbohydrate sialic acid[13]. from the surface membranes of GI cells, this overrides the GI tract’s mucus defence and allows the B subunit to bind to the glycolipid monosialosyl ganglioside (GM1): the receptor of CTX[14].

Once the binding of the B subunit is complete with GM1, the role of this part of the CTX is relatively complete. CTA1 is subsequently able to enter the cell, passing through the membrane.

How CT Causes Disease

Following the toxins entry into the cell and Alpha protomer cleavage, the A1 is trafficked to the endoplasmic reticulum (ER) where it associates with disulphide isomerase (PDI). This triggers the unfolding of the A1 chain and consequently allows it to hijack the ER association degradation mechanism to enter the cytosol by retro-translocation. Normally, proteins which enter the cytosol in this manner are ubiquitinated and then degraded by the proteasome, however, the A1 subunit avoids this fate by rapid refolding[15].

The enzyme then catalyses the transferral of ADP ribose from intracellular NAD+[16] to the G protein alpha subunit (stimulatory G protein), thus activating the particular subunit of the G protein[17]. The A1 can now ribosylate the alpha subunit of a G-protein associated with an intestinal epithelial cell, preventing the hydrolysis of GTP bound to the same G-protein. This locks the G-protein in an active state, leading to the indefinite stimulation of adenylyl cyclase, causing a rise in cAMP concentration. This causes phosphorylation and activation of the cystic fibrosis transmembrane conductance regulator (CFTR protein) leading to the ATP mediated efflux of chloride ions pumped out of the enterocyte[18]. This then causes water, sodium and potassium to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea[19]. This is due to the water potential being drastically lowered in the lumen due to the efflux of ions. Water, therefore, flows out of the epithelial cells surrounding the small intestine, and into the lumen.

Treatment of Cholera

Oral rehydration solutions (ORS) are used to treat cholera, due to their ability to replenish both lost water and electrolytes lost through excretion after ingestion of the cholera toxin. Their components are osmotically similar to that of healthy human blood, perhaps most significantly sodium and glucose. This is because the sodium can be transported into the blood via the sodium-glucose cotransporter protein on cell membranes, moving sodium down its concentration gradient.


  1. Vanden Broeck D, H. C. D. W. M., 2007. Vibrio cholerae: cholera toxin. Int J Biochem Cell Biol, 39(10), pp. 1771-1775.
  2. Dilip Kumar Biswas, Rama Bhunia, Dipankar Maji, and Palash Das, “Contaminated Pond Water Favors Cholera Outbreak at Haibatpur Village, Purba Medinipur District, West Bengal, India,” Journal of Tropical Medicine, vol. 2014, Article ID 764530, 5 pages, 2014. doi:10.1155/2014/764530
  3. 6. Cholera Causes - Mayo Clinic [Internet]. 2015 [cited 22 November 2015]. Available from:
  4. Microbiologyonline. CHOLERA: DEATH BY DIARRHOEA [Internet]. 2015[cited 22 November 2015]. Available from:
  5. Leitch G, Burrows W. Experimental Cholera in the Rabbit Ligated Intestine: Ion and Water Accumulation in the duodenum, Ileum and Colon. Journal of Infectious Diseases [Internet]. 1968;118(4):349-359. Available from:
  6. J S. Cholera toxin - a foe and a friend. - PubMed - NCBI [Internet]. 2015[cited 21 November 2015]. Available from:
  7. Haan, L. and Hirst, T. 2004. Cholera toxin: A paradigm for multi-functional engagement of cellular mechanisms. From Molecular Membrane Biology: Vol. 21/2 pp77-92 [Journal Article] Available at (Accessed 17/11/14)
  8. Daniel J.-F. Chinnapen, H. C. D. S. W. I. L., 2006. Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER. FEMS Microbiology Letters, 266(2), pp. 129-137.
  9. Wellcome Trust. No Date. The biology behind Cholera. [Online] Available at
  10. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at
  11. Palumbo, RN. and Wang, C. 2006. Bacterial invasin: structure, function, and implication for targeted oral gene delivery. From Current Drug Delivery: Vol. 3/1 pp47-53 [Journal Article] Available at
  12. Edited version of CTA1 hydrolysis prevention of GTP to hide Pertussis Toxin - an alternative enterotoxin from Gill and Woolkalis, 1985
  13. Rogers, K. 2009. Neuraminidase. [Encyclopaedia] Available at
  14. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at
  15. Naomi L. B. Wernick, D. J.-F. C. A. C. a. W. I. L., 2010. Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic Reticulum. MDPI, 2(3), pp. 310-325.
  16. Todar's Textbook of Bacteriology by Kenneth Todar PhD (2009). Available at: (last accessed 14/11/15)
  17. B. Alberts, A.Johnson, J.Lewis, D.Morgan, M.Raff, K.Roberts, P.Walter (2014) Molecular Biology of the Cell - 6th Edition, New York: Garland Science
  18. Wayne I. Lencer, T. R. H. R. K. H., 1999. Membrane traffic and the cellular uptake of cholera toxin. Biochimica et Biophysica Acta (BBA), 1450(3), pp. 177-190.
  19. Bruce Alberts, A. J. J. L. M. R. K. R. a. P. W., 2007. Molecular Biology of the Cell, 5th edition. In: Molecular Biology of the Cell, 5th edition. New York: Garland Science, p. 906.
Personal tools