Cholera toxin

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=== Introduction  ===
 
=== Introduction  ===
  
Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the the bacterium ''[[Vibrio cholerae|Vibrio cholerae]]<ref>Vanden Broeck D, H. C. D. W. M., 2007. Vibrio cholerae: cholera toxin. Int J Biochem Cell Biol, 39(10), pp. 1771-1775.</ref>.''&nbsp;CT is the cause of cholera, often from dirty water. CT is transmitted between patients via the fecal-oral route therefore is often found in countries with poor sanitation. The cholera toxin affects the [https://teaching.ncl.ac.uk/bms/wiki/index.php/Epithelial_cells 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&nbsp;characterised by its ability to&nbsp;cause severe diarrhoea, often leading to [https://teaching.ncl.ac.uk/bms/wiki/index.php/Dehydration dehydration]<ref>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</ref>. In extreme circumstances&nbsp;[https://teaching.ncl.ac.uk/bms/wiki/index.php/Cholera cholera ]can lead to death.<br>
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Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the the bacterium ''[[Vibrio cholerae|Vibrio cholerae]]<ref>Vanden Broeck D, H. C. D. W. M., 2007. Vibrio cholerae: cholera toxin. Int J Biochem Cell Biol, 39(10), pp. 1771-1775.</ref>.''&nbsp;CT is the cause of cholera, often from dirty water. CT is transmitted between patients via the fecal-oral route therefore is often found in countries with poor sanitation. The cholera toxin affects the [[Epithelial_cells|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&nbsp;characterised by its ability to&nbsp;cause severe diarrhoea, often leading to [[Dehydration|dehydration]]<ref>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</ref>. In extreme circumstances&nbsp;[[Cholera|cholera]] can lead to death.<br>  
  
 
=== '''''V. cholerae'''''  ===
 
=== '''''V. cholerae'''''  ===
  
<span style="line-height: 1.5em; font-size: 13.28px;">V.Cholerae is a comma shaped, gram negative&nbsp;</span>bacterium and has one flagella at the positioned at the pole of&nbsp;the cell.<ref>4. [Helical growth and the curved shape of&amp;amp;amp;nbsp;Vibrio cholerae t]. 2015 [cited 21 November 2015]. Available from: http://femsle.oxfordjournals.org/cgi/pmidlookup?view=long&amp;amp;amp;amp;pmid=11430401</ref>&nbsp;V.Cholerae, known to lie dormant in water and food supplies&nbsp;that have been contaminated by human excrement are a&nbsp;concern for large scale outbreaks.<ref>6. Mayoclinic.org. Cholera Causes - Mayo Clinic [Internet]. 2015 [cited 22 November 2015]. Available from: http://www.mayoclinic.org/diseases-conditions/cholera/basics/causes/con-20031469</ref> Once V.Cholerae enters its&nbsp;human host, the bacterium propel themselves through the&nbsp;mucus membranes of the ileum attaching themselves to the&nbsp;epithelial lining<ref>Microbiologyonline. CHOLERA: DEATH BY DIARRHOEA [Internet]. 2015[cited 22 November 2015]. Available from: http://www.microbiologyonline.org.uk/media/transfer/doc/factfile_cholera.pdf</ref> releasing CT thus activating a cascade of cell&nbsp;signalling pathways leading to massive fluid loss from the&nbsp;ileum and duodenum.<ref>Leitch G, Burrows W. Experimental Cholera in the Rabbit Ligated Intestine: Ion and Water Accumulation in theDuodenum, Ileum and Colon. Journal of Infectious Diseases [Internet]. 1968;118(4):349-359. Available from: http://www.jstor.org/stable/30102134?seq=2#page_scan_tab_contents</ref>&nbsp;V.cholerae secretes the enterotoxin CT in a very efficient&nbsp;manner with more than 90% of the toxin found extracellularly. CT, once secreted into a system, initiates its toxic&nbsp;action by means of binding to high affinity cell membrane receptors identified to be the ganglioside or GM1&nbsp;receptors.<ref>J S. Cholera toxin - a foe &amp;amp;amp;amp; a friend. - PubMed - NCBI [Internet]. Ncbi.nlm.nih.gov. 2015[cited 21 November 2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21415489</ref>  
+
''<span style="line-height: 1.5em; font-size: 13.28px;">V. cholerae</span>''<span style="line-height: 1.5em; font-size: 13.28px;"> is a comma shaped, gram negative&nbsp;</span>bacterium and has one flagella at the positioned at the pole of&nbsp;the cell.<ref>4. [Helical growth and the curved shape of&amp;amp;amp;amp;nbsp;Vibrio cholerae t]. 2015 [cited 21 November 2015]. Available from: http://femsle.oxfordjournals.org/cgi/pmidlookup?view=long&amp;amp;amp;amp;amp;pmid=11430401</ref>&nbsp;V.Cholerae, known to lie dormant in water and food supplies&nbsp;that have been contaminated by human excrement are a&nbsp;concern for large scale outbreaks.<ref>6. Mayoclinic.org. Cholera Causes - Mayo Clinic [Internet]. 2015 [cited 22 November 2015]. Available from: http://www.mayoclinic.org/diseases-conditions/cholera/basics/causes/con-20031469</ref> Once V.Cholerae enters its&nbsp;human host, the bacterium propel themselves through the&nbsp;mucus membranes of the ileum attaching themselves to the&nbsp;epithelial lining<ref>Microbiologyonline. CHOLERA: DEATH BY DIARRHOEA [Internet]. 2015[cited 22 November 2015]. Available from: http://www.microbiologyonline.org.uk/media/transfer/doc/factfile_cholera.pdf</ref> releasing CT thus activating a cascade of cell&nbsp;signalling pathways leading to massive fluid loss from the&nbsp;ileum and duodenum.<ref>Leitch G, Burrows W. Experimental Cholera in the Rabbit Ligated Intestine: Ion and Water Accumulation in theDuodenum, Ileum and Colon. Journal of Infectious Diseases [Internet]. 1968;118(4):349-359. Available from: http://www.jstor.org/stable/30102134?seq=2#page_scan_tab_contents</ref>&nbsp;V.cholerae secretes the enterotoxin CT in a very efficient&nbsp;manner with more than 90% of the toxin found extracellularly. CT, once secreted into a system, initiates its toxic&nbsp;action by means of binding to high affinity cell membrane receptors identified to be the ganglioside or GM1&nbsp;receptors.<ref>J S. Cholera toxin - a foe &amp;amp;amp;amp;amp; a friend. - PubMed - NCBI [Internet]. Ncbi.nlm.nih.gov. 2015[cited 21 November 2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21415489</ref>  
  
 
=== Structure of the Toxin&nbsp;  ===
 
=== Structure of the Toxin&nbsp;  ===

Revision as of 16:50, 19 October 2016

Contents

Introduction

Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the the bacterium Vibrio cholerae[1]. CT is the cause of cholera, often from dirty water. CT is transmitted between patients via the fecal-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 flagella at the positioned at the pole of the cell.[3] V.Cholerae, known to lie dormant in water and food supplies that have been contaminated by human excrement are a concern for large scale outbreaks.[4] Once V.Cholerae enters its human host, the bacterium propel themselves through the mucus membranes of the ileum attaching themselves to the epithelial lining[5] releasing CT thus activating a cascade of cell signalling pathways leading to massive fluid loss from the ileum and duodenum.[6] 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.[7]

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 [8]  and located at the centre of the toxin whilst the [9]. The five Beta subunits are arranged into a pentameric ring and are responsible for binding the toxin to a cell's membrane[10], weighing 11kDa each, binds to five ganglioslide GM1 receptors on the plasma membrane and trigers endocytosis of the toxin, whilst the Alpha subunit is made up of an A1 and A2 chain. A1 is enzymatic and does most of the work, once inside the cell. A2 is an extended alpha helix, connceting 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[11].  

Mechanism of Infection

The location of CTX’s function is found in the lumen of the small intestine[12], where, in an effort to infect cells, the bacterium vibrio cholerae produces an invasin[13]. 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[14].
Cholera Toxin entering cell membrane via GM1.
[15]

Neuraminidase is produced by cholera cells as an invasin, neuraminidase is part of a group of enzymes responsible for removing the carbohydrate sialic acid[16] 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[17].

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[18].

The enzyme then catalyses the transferral of ADP ribose from intracellular NAD+ [19] to the G protein alpha subunit (stimulatory G protein), thus activating the particular subunit of the G protein. [20] The A1 can now ribosylates 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. [21]This then causes water, sodium and potassium to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea[22]. 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. 

References

  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. 4. [Helical growth and the curved shape of&amp;amp;amp;nbsp;Vibrio cholerae t]. 2015 [cited 21 November 2015]. Available from: http://femsle.oxfordjournals.org/cgi/pmidlookup?view=long&amp;amp;amp;amp;pmid=11430401
  4. 6. Mayoclinic.org. Cholera Causes - Mayo Clinic [Internet]. 2015 [cited 22 November 2015]. Available from: http://www.mayoclinic.org/diseases-conditions/cholera/basics/causes/con-20031469
  5. Microbiologyonline. CHOLERA: DEATH BY DIARRHOEA [Internet]. 2015[cited 22 November 2015]. Available from: http://www.microbiologyonline.org.uk/media/transfer/doc/factfile_cholera.pdf
  6. Leitch G, Burrows W. Experimental Cholera in the Rabbit Ligated Intestine: Ion and Water Accumulation in theDuodenum, Ileum and Colon. Journal of Infectious Diseases [Internet]. 1968;118(4):349-359. Available from: http://www.jstor.org/stable/30102134?seq=2#page_scan_tab_contents
  7. J S. Cholera toxin - a foe &amp;amp;amp;amp; a friend. - PubMed - NCBI [Internet]. Ncbi.nlm.nih.gov. 2015[cited 21 November 2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21415489
  8. larger (240 amino acids) consists of two domains (A1 and A2)
  9. smaller five B subunits (103 amino) acids is located peripherally
  10. 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 http://informahealthcare.com/doi/abs/10.1080/09687680410001663267 (Accessed 17/11/14)
  11. 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.
  12. Wellcome Trust. No Date. The biology behind Cholera. [Online] Available at http://bigpictureeducation.com/biology-behind-cholera
  13. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at http://textbookofbacteriology.net/cholera.html
  14. 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 http://www.ncbi.nlm.nih.gov/pubmed/16472093
  15. Edited version of CTA1 hydrolysis prevention of GTP to hide Pertussis Toxin - an alternative enterotoxin from Gill and Woolkalis, 1985
  16. Rogers, K. 2009. Neuraminidase. [Encyclopaedia] Available at http://www.britannica.com/EBchecked/topic/1093141/neuraminidase
  17. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at http://textbookofbacteriology.net/cholera.html
  18. 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.
  19. Todar's Textbook of Bacteriology by Kenneth Todar PhD (2009). Available at: http://textbookofbacteriology.net/cholera_3.html (last accessed 14/11/15)
  20. 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
  21. 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.
  22. 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.
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