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No love in the time of cholera.

By Brooke Napier

It’s no secret by now that one of my very favorite topics in science is the idea that many bacterial species have co-evolved with humans to become successful pathogens, aka super ninja killing machines.

Since this is HUGE topic with WAY too many cool avenues, I want to focus on one (very smart) bacterial species that laughs in the face of the human immune system: Vibrio cholerea. Dun dun DUN!

Old school, yo.

Vibrio cholerea is the causative agent of the horribly unpleasant, life threatening diarrheal disease cholera.

Yes, I’ve heard of cholera, but what is cholera?

Cholera is an acute diarrheal disease caused by an infection of the intestines by the bacterium Vibro cholerae. V. cholerae likes to hid out in water or food that have been contaminated by feces, that way it can be ingested by unsuspecting humans and wreak havoc in the intestines (seems like a scary trip from the mouth to the intestines, right? Lots of enzymes, lowered pH, etc… this will be important later).

Fortunately the advancement of water treatment (specifically chlorination and filtering), spearheaded by John Snow in England during the late 1800’s after identifying that contaminated water caused an increase in cholera incident, has allowed the US to evade a serious cholera outbreak within the last 100 years.

However this disease is still rampant throughout developing countries. Specifically, there are around 3-5 million cases an over 100,000 deaths per year due to cholera.

That is why V. cholerae is still a problem, but how is it such a ninja?

One of the way pathogenic bacteria have evolved to be replicating-puss-inducing badasses is by detecting when they’re inside of a human. They can do this by sensing temperature change (inside is warmer than outside), lowered pH (in the stomach), differential concentrations of ions (iron is limiting in the innate immune cells), etc. They sense these environmental changes with the use of highly sophisticated signal transduction systems – or a very tiny form of telephone.

Briefly, bacteria have a sensor on their outer membrane that can detect these environmental changes. In response to changes this sensor protein phosphorylates itself (autophosphorylates). This phosphate group acts as the secret password to inform the inside of the cell things have changed! Next, this phosphorylated sensor protein transfers this phosphate group to its buddy in the cell, good ole’ response regulator. Response regulator then controls the expression of “holy-crap-protect ourselves” genes, or… you know, some genes that contribute to protecting the bacteria in whatever environment it sense. 

Above is a very well described two-component system that responds to influxes in cationic antimicrobial peptides (positively charged antibacterial peptides).

PhoQ (sensor protein) senses environmental changes, which then passes on the message (phosphate – P) to PhoP (response regulator) that now can increase expression of genes that will modify the bacterial membrane to make it more positive (to avoid confrontation with the cationic antimicrobial peptides).

That’s just one of many, but back to our story on V. cholerae!

V. cholerae is well known, and feared, for it’s very-toxic-to-humans: Cholera toxin (CT). CT is what makes V. cholerae so prone to causing disease, specifically it’s to blame for the diarrhea characteristic of cholera.

So wouldn’t it be interesting if V. cholerae could increase expression of CT in response to some type of environmental change indicative of the human body?

 Menghua Yang et al., were asking the same question. You will never believe how they did this…

1)   They created a strain of V. cholerae that lights up (literally) when it is expressing TcpA (response regulator that is incharge of increasing expression of CT).

2)   They took a mouse’s intestines and cut them up in very small chunks and put each of the individual chunks into a test tube with the light-up V. cholerae. Essentially, if the V. cholerae lights up in the presence of specific chunks of the intestines this means that CT is being expressed, and they can trace back the chunk of intestine to the map of the intestine and know what part of the mouse intestine increases expression of CT. BRILLIANT.

3)   They took the small intestine of infant and adult mice and found that something in these pieces of the intestine trigger CT expression. So they took the small intestines of these mice and identified some small molecules that were present within these samples by thin-layer chromatography (for a description of this method follow this link).

4)   BILE SALTS. That is what they found induces the expression of CT. The presence of bile salts influenced the expression of this very potent toxin that causes the worse symptoms of cholera. Amazing.

5)   Not only that, TcpA (the response regulator that is in charge of increasing expression of CT) needs to be dimerized to increase expression of CT, and they show that bile salts from the small intestines can induce the di-sulfide bonds that hold TcpA dimers together.

 I'm pretty sure they have no idea what protein is sensing bile salt, so you can name that protein whatever you'd like.

Essentially, V. cholerae monitors normal host digestive systems to up-regulate it’s virulence, or disease-causing, cascades.

It is highly likely that there are other environmental signals that contribute to the increased expression of CT, but this is a very good first step at understanding this ninja-of-a-bacteria.  

My guess, as well as the author’s, is that other intestinal pathogens can control their virulence cascades by bile salts as well – to the lab!

ResearchBlogging.orgYang M, Liu Z, Hughes C, Stern AM, Wang H, Zhong Z, Kan B, Fenical W, & Zhu J (2013). Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence. Proceedings of the National Academy of Sciences of the United States of America, 110 (6), 2348-53 PMID: 23341592

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Reader Comments (3)


So do biologists have any idea why bile salts in particular? Like what made them conducive to making Cholera develop this sensitivity?

February 18, 2013 | Unregistered CommenterSarah Scoles

Yes this is write

May 4, 2015 | Unregistered CommenterJitendra

Really Good content. Follow here and enjoy!

July 19, 2017 | Unregistered CommenterAppspcwin

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