Cholera Toxin aka Protein of the Year

Source:  Cholera Toxin aka Protein of the Year    Tag:  cause of cholera disease

Figure 1: Secondary Structures of the Cholera toxin (Made on PyMol, PDB: 1XTC)

History

Every year 3 to 5 million people are diagnosed with Cholera and 120,000 die. With a fast incubation period of a couple hours to a couple days, Cholera is a disease that has had a major impact in both our past and present.

Originally described in 1500, it is expected that cholera-like symptoms date back to the time of Hippocrates and the Buddha. In the 19th century Cholera made its first world tour with a start in India. Since then there have been 6 more pandemic outbreaks in the world killing millions of people.


Figure 2: The locations of the seven pandemic outbreaks 
(http://laosaikia-cholera.blogspot.com/p/history.html)

Since the last pandemic outbreak in 1960's and 1970's, there have been various other outbreaks with most concentrating in Central and South American and Africa.


Figure 3: Locations of outbreaks since 1980. Many in South America and Africa
(http://www.who.int/gho/epidemic_diseases/cholera/en/)

These pandemics and outbreaks are not just a health concern, but also and economic nightmare. They cause panic and concern among the population and the world. This panic leads to tighter regulations on trade and travel. An example of this is in 1991, Peru had an outbreak which led to a loss of 770 million dollars due to food trade embargoes with various countries. So Cholera does not only effect the patient's health but also the societies they live in.

Treatment

But this story is not all doom and gloom. Today we live in a country which has taken the necessary steps to prevent Cholera almost completely. Historically this was not the case.  With the cause of this disease unknown until the late 1800s, until a connect to contaminated water was made by John Snow. This caused cities in many developed countries to separate sewage and drinking water. This significantly decreased cases by 1900 in many developed countries. In 1960's the main treatment of oral or IV rehydration was set in place by Robert Allen Philips saving millions of lives. By rehydrating with rehydration salts replaces the fluids that were lost with diarrhea and vomiting and preventing dehydration. Antibiotics are only used in very severe cases to reduce diarrhea and the spread of the bacteria.  

How it works
When Vibrio cholerae enters the intestines the B subunit attaches to the epithelial cells or any other cells that have ganglioside GM1. GM1 acts a a binding point for Cholera Toxin (Fig. 4). Once bound to the cell Subunit A is placed into the cell and activated by reduction of a disulfide bond (As seen in Figure 5C). 



Figure 4: Globular structure of Cholera Toxin on the cell 
(http://www.bmsc.washington.edu/WimHol/figures/figs2/WimFigs2.html)



Figure 5: A: Secondary structures broken down into subunits
B &C: Showing the Subunits and specifically looking at A1 and A2
(http://www.mdpi.com/toxins/toxins-02-01445/article_deploy/html/images/toxins-02-01445-g001.png)

Once Subunit A is in the cytosol and activated, A1 subunit binds to a NAD+. This leads to ADP ribosylation of GTP-binding protein alpha subunit which permanently activates the protein and adenylate cyclase.  The activation of AC then leads to increase on cAMP production.


Figure 6: Effect of A1 subunit within the cell and the increase in cAMP
(http://intranet.tdmu.edu.te.ua/data/cd/disk2/images/fig24_5.jpg)

The increase in cAMP and prostaglandins by the infected cell leads to a increase in water and salt in the intestinal lumen which lead to the common symptoms of the disease, diarrhea and dehydration. 

Summary

Through taking the necessary steps with water treatment and control it has lead to diseases such as Cholera becoming forgotten in many societies. This has lead to many lives being saved throughout the world.
(https://imgflip.com/i/7k5fp)
With continued efforts to teach rehydration and waste treatment not only can Cholera be completely eradicated, but also many other disease also.

No other disease as made an impact on the world like Cholera. Through spanning generation and continents, this small toxin has changed the course of history and the way we view the world. This is all thanks to the subunits and infiltration mechanism of the Cholera Toxin. No other protein has made an impact as large and intense as 1XTC, the Cholera Toxin



Websites:
"Cholera: Causes, Symptoms, Treatment, and Prevention." WebMD. WebMD, 29 Dec. 2014. Web. 14 Mar. 2015.
"Cholera." WHO. N.p., Feb. 2014. Web. 9 Mar. 2015.
"Global Epidemics and Impact of Cholera." WHO. N.p., n.d. Web. 10 Mar. 2015.
Primary Sources:
Page, Kathleen. "Cholera: Mechanism of Infection, History and Treatment." South Carolina Journal of Molecular Medicine 5.26 (2004): n. pag. Web. 10 Mar. 2015.
Savarino, Stephen. "A Legacy in 20th-Century Medicine: Robert Allan Phillips and the Taming of Cholera." Infectious Diseases Society of America 35.6 (2002): n. pag. National Center for Biotechnology Information. U.S. National Library of Medicine, Sept. 2002. Web. 10 Mar. 2015.
Schild, Stefan, Anne Bishop, and Andrew Camilli. "Ins and Outs of Vibrio Cholerae." American Society for Microbiology (2008): n. pag. Mar. 2008. Web. 10 Mar. 2015.

Spangler, Brenda. "Structure and Function of Cholera Toxin and the Related Escherichia Coli Heat-labile Enterotoxin." American Society for Microbiology 56.4 (1992): 622-47. Microbiology and Molecular Biology Reviews. American Society for Microbiology, 1 Dec. 1992. Web. 14 Mar. 2015.