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 transmitted between patients via the fecal-oral route and is often found in countries with poor sanitation. CT is&nbsp;characterised by its ability to&nbsp;cause severe diarrhoea, often leading to 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>.<br> <sup></sup>
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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 transmitted between patients via the fecal-oral route and is often found in countries with poor sanitation. CT is&nbsp;characterised by its ability to&nbsp;cause severe diarrhoea, often leading to 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>.<br> <sup></sup>  
  
 
=== Structure of the Toxin&nbsp;  ===
 
=== Structure of the Toxin&nbsp;  ===
  
CT is a member of the AB5 family of toxins&nbsp;and consists of subunits, Alpha and 5 Beta. The Beta subunits are responsible for binding the toxin to a cell's membrane<ref>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]
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CT is a member of the AB5 family of toxins&nbsp;and consists of subunits, Alpha and 5 Beta. The Beta subunits are responsible for binding the toxin to a cell's membrane<ref>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]fckLRAvailable at http://informahealthcare.com/doi/abs/10.1080/09687680410001663267 (Accessed 17/11/14)</ref>, weighing 11kDa each, binds to five ganglioslide GM1 receptors on the plasma membrane&nbsp;and trigers&nbsp;[[Endocytosis|endocytosis]]&nbsp;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|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<ref>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.</ref>. &nbsp;  
Available at http://informahealthcare.com/doi/abs/10.1080/09687680410001663267 (Accessed 17/11/14)</ref>, weighing 11kDa each, binds to five ganglioslide GM1 receptors on the plasma membrane&nbsp;and trigers&nbsp;[[Endocytosis|endocytosis]]&nbsp;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|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<ref>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.</ref>. &nbsp;
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=== Mechanism of Infection ===
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The location of CTX’s function is found in the [[Lumen|lumen]] of the [[Small_intestine|small intestine]]<ref>Wellcome Trust. No Date. The biology behind Cholera. [Online]
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Available at http://bigpictureeducation.com/biology-behind-cholera</ref>, where, in an effort to infect [[Cell|cells]], the [[Bacteria|bacterium]] vibrio cholerae produces an invasin<ref>Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online]
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Available at http://textbookofbacteriology.net/cholera.html</ref>. The gastrointestinal (GI) tract is coated with a [[Mucus|mucus]] lining with the aim to prevent [[Pathogens|pathogens]] such as CT from entering the [[Endothelial_cell|endothelial cells]] of the gut lining<ref>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]
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Available at http://www.ncbi.nlm.nih.gov/pubmed/16472093</ref>.
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[[Neuraminidase|Neuraminidase]] is produced by cholera cells as an invasin, neuraminidase is part of a group of enzymes responsible for removing the carbohydrate sialic acid<ref>Rogers, K. 2009. Neuraminidase. [Encyclopaedia]
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Available at http://www.britannica.com/EBchecked/topic/1093141/neuraminidase</ref> 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|glycolipid]] monosialosyl ganglioside (GM1): the receptor of CTX<ref>Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online]
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Available at http://textbookofbacteriology.net/cholera.html</ref>.
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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 [[Cell_membrane|membrane]].
  
 
=== How CT Causes Disease  ===
 
=== How CT Causes Disease  ===

Revision as of 12:20, 28 November 2014

Contents

Introduction

Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the the bacterium Vibrio choleraeUNIQ779313615d7ab483-nowiki-00000001-QINU1UNIQ779313615d7ab483-nowiki-00000002-QINU. CT is transmitted between patients via the fecal-oral route and is often found in countries with poor sanitation. CT is characterised by its ability to cause severe diarrhoea, often leading to dehydration[2].

Structure of the Toxin 

CT is a member of the AB5 family of toxins and consists of subunits, Alpha and 5 Beta. The Beta subunits are responsible for binding the toxin to a cell's membrane[3], 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[4].  

Mechanism of Infection

The location of CTX’s function is found in the lumen of the small intestine[5], where, in an effort to infect cells, the bacterium vibrio cholerae produces an invasin[6]. 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[7].

Neuraminidase is produced by cholera cells as an invasin, neuraminidase is part of a group of enzymes responsible for removing the carbohydrate sialic acid[8] 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[9].

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[10].

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. [11]This then causes water, sodium and potassium to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea[12]. This is due to the water potential being dratically lowered in the lumen due to the eflux 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. 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]fckLRAvailable at http://informahealthcare.com/doi/abs/10.1080/09687680410001663267 (Accessed 17/11/14)
  4. 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.
  5. Wellcome Trust. No Date. The biology behind Cholera. [Online] Available at http://bigpictureeducation.com/biology-behind-cholera
  6. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at http://textbookofbacteriology.net/cholera.html
  7. 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
  8. Rogers, K. 2009. Neuraminidase. [Encyclopaedia] Available at http://www.britannica.com/EBchecked/topic/1093141/neuraminidase
  9. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online] Available at http://textbookofbacteriology.net/cholera.html
  10. 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.
  11. 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.
  12. 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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