Don't Drink That Water!!!

I'm sure everyone remembers the powerful earthquake that struck Haiti in 2010. The 7.0 magnitude earthquake ravaged the Haitian landscape leaving cities and people in ruin. Beside the obvious destruction the earthquake produced it also brought about serious health risks. I remember watching the news and seeing these families in tent cities. Anderson Cooper, of course, interviewing the people and giving the world a view of unimaginable poverty (his infamous black shirt is depicted right being given a medal for spreading fear). At the same time I thought, "these people are going to get sick. It may not happen today, or tomorrow, but at some point an outbreak of something will occur." In December 2010 an outbreak of cholera began, marking the beginning of the one of the worst cholera epidemics in modern times.

The story of cholera has its origins way back in history. Like many other illnesses, people in the 19th century knew the disease cholera. In fact it was the first reportable disease in U.S. history. In 1854, the world changed with the use of keen observation. Throughout history, diseases like the plague were thought to have two sources. One was God and the other was the miasma theory. The first being that God punishes humanity by means of disease and the second being that the deadly fumes from swamps and the dead bring about disease. A English physician named John Snow was skeptical to the miasma theory of disease and being the good physician he was decided to investigate the clusters of cholera outbreaks in England.  He used a map and plotted the locations are those infected. Then he placed this map over a map showing the drinking water system throughout London. He saw that every infected area drew its water from a single well. After debate with authorities, Snow finally got them to close the well and like magic the incidence of cholera dropped. It's because of this simple observation that Snow became the father of epidemiology, a path that I would like to follow some day myself.

From the observation that sewage contaminated water was the source of disease, Robert Koch (the man! see the first post. He's the one with the sweet beard!) used his own methods to show that cholera was in fact caused by a bacteria. Just like anthrax, cholera was not transmitted by a miasma but a bacillus that named vibrio cholerae. Together Snow and Koch developed the fundamentals of bacteriology and epidemiology: Infectious diseases are caused by bacteria and each one was a particular route of infection.

If yersinia pestis is the Black Death then vibrio cholerae is surely the White Death. The reason is simple enough, it causes a sever diarrhea that is white. Yes I'll say that again it's white, like rice water, hence the condition called Rice Water stool. It doesn't have a smell nor a color. Essentially it's just water that is leaving the body. If left untreated it will probably kill the host. This is why many cartoons were made in the early 20th century that portray cholera as Death or Death spreading cholera. I love the top of that picture the most, it made me laugh.

The pathogenesis of vibrio cholerae begins with its two plasmids. These plasmids contain two pathogenicity islands (clusters of genes coding for virulence traits) coding for the toxin and an adhesin respectively. Interestingly, the clusters of genes coding for the toxin are now believed to have been derived from a bacteriophage that injected its genes into a harmless virbio. The bacteria is initially ingested and then adheres to the epithelial lining of the intestinal tract. This is why it has the adhesins. The next thing that occurs is the secretion of the cholera toxin.

So, vibrio cholerae secretes the toxin into the environment. This toxin has a ton of individual components but can be broken down into two main parts. The first is the receptor binding domain (B domain), which is a series of five peptide subunits that act together for the toxin to bind to the GM1 ganglioside on the surface of the intestinal epithelial cell. I know, I know...a ganglio-wha? It's essentially a sugar molecule that extends off the host which it uses for signalling with other cells. Anyway, once it binds the GM1 ganglioside the cell takes the toxin up via endocytosis like it would to anything else that gets bound. Inside the vesicle, the receptor binding domain releases from the catalytic domain (A domain), the part of the toxin that ends up doing the damage. The A domain passes through the B domain which releases the A part into the cellular cytoplasm. The picture to the left shows the cholera toxin with the B domain on the bottom and the A domain on the top.

Now the story get's cool. If you read the e. coli post this'll sound familiar. So, the toxic A domain ADP-ribosylates a G protein on the inside surface of the cell membrane. By adding this small molecule the G protein can no longer regulate the enzyme adenylate cyclase by turning it off. The result is that this enzyme stays on, and makes a large amount of the molecule cAMP. This molecule acts on ion channels causing ions within the cell like K+, Ca 2+, and Na+ to leave the cell. Due to osmotic force, water inevitably follows and leaves the cells. The water goes into the intestinal lumen and this is the source of the "rice water stool" seen left. Not pretty...

The result of this drop in water volume leads to hypovolemic shock which leads to kidney failure and death. It's for this reason that physicians use a series of ions including sugar as treatment. Interestingly, the sugar channels are not effected by the toxin, so by bringing sugar into the cell water will follow and flow back into the cell hopefully stopping the watery diarrhea. Super clever! We can use osmolarity against the disease which is ruled by osmolarity! What's important is that they replace the amount of water that is lost. In order to do this clinics use the so called "cholera cot." It's a cot with a hole in it with a bucket that measures the amount of water that is expelled from the body. Very simple but super effective!

Cholera remains as a disease exacerbated by poverty. Indeed cholera is a disease not commonly found in the modern world, but runs rampant through underdeveloped nations where human waste contaminates the drinking water. Luckily, it's an easily treatable disease and if treatment is given promptly and effectively it should be cleared on its own. Antibiotics are usually not prescribed unless it is severe. 

Vibrio cholerae has played a serious role in history effectively shaping how epidemiologist started to understand how bacterial diseases are spread. Importantly, in modern times Horizontal Gene Transfer has resulted in the transfer of the cholera toxin to previously avirulent types of bacteria like e. coli. Likewise, this same process resulted in vibrio's acquisition of the toxic genes in the first place! In the wondrous world of biology we have to appreciate how these bacteria evolve so quickly. We also have to recognize that in order to address the spread of these diseases we need to help nations with simple necessities like clean drinking water.