The Man of Many Hats

I was thinking about pathogens for a new blog post while biting into a delicious, 100% angus beef burger the other day and thought about the kinds of organisms that could be hiding within. Of course the chances are remote but I thought about infections of Escherichia Coli...that's the last time I'm going to try spelling that word! As a result, I decided to post a little bit about this bacteria. Crazy enough, I read on the news today that 14 people have died and hundred are sick in Germany and across Europe due to contaminated cucumbers so this post fits perfectly with a current event.


What few recognize is that e.coli isn't this horrible pathogen that inflicts disease whenever you have it within your gut. In fact, everyone has billions of these organisms sitting in their colon right now and they're definitely NOT making anyone sick. More importantly these bacteria are supposed to be there to help digestion by breaking down cellulose from plants that humans eat. Humans can't digest this material (aptly named "insoluble fiber" on the nutrition facts on the product label) so the bacteria that are harbored in your gut are beneficial to you. Disturbing this balance can increase the risk of other types on conditions, but I'll save those for another post.

So what gives e.coli such a bad rap? The answer to that starts with an incident that happened in 1982 with a restaurant food chain. The hamburgers that were served harbored a dangerous strain of e.coli that was ingested by customers leading to deadly gastrointestinal problems combined with kidney failure. Some of those infected died and e.coli suddenly became a bacteria to be feared. Isn't the media a wonderful thing?

Ok, great, so what made that bacteria so deadly compared to the ones in your gut right now? The best way to answer this is seen in the 6, yes that's right 6, kinds of pathogenic e.coli. I'll only explain 4 of them because little is known about the last two and these four and are the primary cause of disease in humans. The difference, the presence or absence of various virulence factors that mediate disease.

The first in Enterotoxigenic e.coli or ETEC (E-teck). This causes what many call "Traveler's Diarrhea" or, if you're in Mexico, "Monteczuma's Revenge." It's the leading cause of bacterial diarrhea in developing countries as well due to contamination of drinking water with run-off from waste. This form of e.coli has acquired two virulence factors from horizontal gene transfer, a nifty trick that also deserves its own post. At some point in the bacteria's evolution, it acquired the genes coding for two toxins called the heat-labile toxin (LT seen below with fancy colors) and the heat-stable toxin (ST). The LT acts very similarly to the cholera toxin providing further evidence for an acquired virulence factor from a different bacteria. The LT functions by adding a ADP-ribose molecule (right), which is modified from NAD (the top part of the molecule on the right) used in normal cellular metabolism, to a special kind of protein within the host cell membrane called a G protein. These G proteins functions to regulate other proteins in the membrane that further act upon ion channels using a molecule called cAMP. What happens here is that the addition of this ADP-ribose molecule causes the G Protein to become constantly activated. This eventually deregulates the ion channels by having way too much cAMP around, which leads to more salt ions in the intestinal lumen of the host organism. In order to balance the increase in salt, water flows out of the cell and into the intestinal lumen which leads to diarrhea...super fun! The ST works in a similar manner but instead of an increase in cAMP, there is an increase in cGMP but the result is the same.

The next is the one that has caused the raucous. It's known as Enterohemorragic e.coli or EHEC. The model system for these strains is e.coli O157:H7 and this is the same bacteria isolated from the patients that ate at the food chain in 1982. Here again, the culprit is the aquisition of a virulence factor from a different bacteria. In this case the bacteria acquired the Shiga toxin (left)  from a closely related bacterial pathogen called shigella. What separates this from ETEC is the fact that EHEC actually kills the intestinal cells they infect. The shiga toxin cleaves 28s RNA (what the hell is that!?).  28sRNA is a necessary part of a ribosome which translates proteins from the mRNA the cell makes from DNA. Another rule in biology : If you (the cell) can't make protein, you (the cell) die! So by getting rid of 28sRNA the cell not longer produces proteins and dies which leads to the destruction of the instestinal tract and the bloody diarrhea found in these patients. It is also associated with a condition called hemolytic uremic syndrome wherein blood cells are destroyed leading to acute kidney failure which is very bad.


The third form of e.coli is Enteropathogenic or EPEC. This strain is super cool. Intestinal cells don't have the necessary receptor to mediate proper attachment of the bacteria. This isn't good for the bacteria so it cleverly has a gene that codes for the its own receptor called TIR. The bacteria then uses a syringe-like molecular machine that injects the receptor directly into the host cell! The receptor then migrates to the membrane and, shazam, the bacteria can now attach to the cell to mediate disease via the intimin protein on the bacterial membrane. Disease is caused by the syringe-like machine injecting other proteins that mess with the host cell membrane, specifically by forming a pedestal on which the bacteria sits (left)...sounds weird but it's true and it's awesome! By screwing with the cell membrane, the intestinal tract loses the tightly bound and organized structure formed by these cells and the result is poor absorption of water leading to diarrhea...super fun!

The final strain is Uropathogenic or UPEC. This strain of bacteria caused urinary tract infection! Here the e.coli has acquired a different set of factors. They have the P pilus which is a protein that is designed to specifically bind to bladder and urethral cells. The result is that these bacteria can ascend the urinary tract and, if given the chance, infect the bladder or even the kidneys. These infections are fought off by the induction of the inflammatory response of the body, and the result is the burning and pain associated with a UTI. Interestingly, this strain has developed a unique way of preventing being eaten by the body's macrophages. The bacteria elongate outward (pic right) and the macrophages can no longer extend enough to take them up! Evolultion ftw! The problem comes when these bacteria infect the kidneys, a condition called pyelonephritis. Inflammation here is very bad!


Wonderful, so what's the point here? Well, first, e. coli is awesome in its diversity. But more importantly, these are the same bacteria which differ only in the set of virulence factors they contain. Not having any factors means the bacteria can't do anything and is harmless. But thanks to horizontal gene transfer between bacteria, e.coli has developed novel ways of causing disease in humans. Increasing the diversity within the e.coli population is evolutionarily beneficial to the bacteria because it allows the bacteria to infect and survive in a different niche within the host, as best shown in UPEC which infects the urinary tract instead of the GI tract. Also, in the case of enteric e.coli (ones that infect the GI tract) diarrhea can also be seen as a potential benefit because it increases the chance of the host organism shedding the bacteria into the environment and allowing uptake by other organisms by the fecal-oral route...gross, but more common than you think!


The moral of the story is simple. The variation of diseases caused by bacteria are caused by the acquisition of virulence factors which can turn a previously avirulent strain of bacteria into a potentially deadly one. It's important to understand this principle if the influence of evolution on a pathogen is to be understood. As you will soon see, bacteria develop ways of swapping bits of genetic information in order to increase fitness and the result is new strains of pathogenic bacteria that were once harmless.