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The Trigger That Turns C. difficile Into A Killer

03/01/2015 08:38 EST | Updated 05/01/2015 05:59 EDT

Over a decade has passed since public health officials sounded the alarm over the bacterium, Clostridium difficile. The concern originated in 2003-2004, when an outbreak in Quebec led to over 7,000 cases and over 1,200 deaths. Further surveillance revealed cases all across North America with at times over one-fifth dying from the disease.

But C. difficile wasn't necessarily lethal. Analyses conducted by researchers revealed the presence of toxins, known simply as A and B. When they were present, the bacterium was 20 times more harmful. With increased surveillance, the link between the toxin and a higher chance of worsening disease and death was established. As a result, the toxin itself became a focus for several researchers aiming to stop the scourge.

One of the primary goals in understanding how the bacterium used its toxin to cause disease focused on the nature of bacterial growth in the body. After all, not everyone who was exposed ended up with illness. The first major discoveries revealed the toxin was not produced all the time. Instead, it was triggered when there was a change in the microenvironment.

The initial focus was the availability of nutrients. Depending on the level of sugars, fats, and amino acids, the bacterium would either live comfortably without causing any harm or somehow turn on the toxin-producing machine. The most interesting revelation involved the observation of lower toxin production in the presence of higher levels of glucose, the basic sugar we all use for energy. Although the finding was considered to be interesting, in terms of developing a potential mechanism for toxin there was still little help.

There was, however, a theory accompanying the observations. If the external levels of glucose and other nutrients played a role in the production of toxin, then there had to be a signal which the cells produced to notify the entire population of the need to either sit back and enjoy or get ready for battle. The concept is better known as quorum sensing (QS) and for the last twenty years, it's been regarded as the base for microbial communication.

The exact process of QS differs for many bacteria but they all appear to follow a similar path. As the microbe explores the environment, it can sense, much like a nose, the levels of various factors, such as food sources and potential treats. Depending on what exists on the outside, the bacterium will tend to release chemicals into the environment. When other bacteria come into the contact with this signal, they react in a particular manner. This can include increasing or decreasing their rate of growth, production of certain chemicals, or even the initiation of movement to escape a potentially harmful environment.

Although no such mechanisms had been found in C. difficile, particularly for onset of disease, researchers continued to hunt one down. After all, most opportunistic pathogens had similar types of cell-to-cell communication; why should this bacterium be different? Last week, an American team of researchers finally found evidence of QS. Even more important was how one particular molecule could command both toxin production and the onset of an attack.

At first, the group wanted to find out if QS even existed and performed a simple experiment to determine whether they were looking in the right direction. All they did was take the environmental liquid from one C. difficile culture and then added it to another fresh petri plate containing bacteria not yet producing the toxin. As expected, they were able to spark toxin production. But there was a catch; the cells only made the toxin when exposed to liquid from aging cultures. In other words, the trigger for toxin production had to do with a waning nutrient supply.

This result partially explained the reasoning behind the lack of illness in all people who are exposed. In order to make toxin, the bacteria had to be in a high enough concentration to deplete nutrients. In the gut, they cannot grow to these levels unless there is some type of alteration in the diversity and numbers of bacteria in the gut. This usually happens when medications such as antibiotics are used; the bacterial population drops and C. difficile has the ability to thrive.

With this information in hand, the team wanted to identify the QS factor involved. They developed several types of isolation experiments in order to find the trigger. Eventually, they were able to isolate one particular molecule, which they called Toxin-Inducing Signal (TI). Although no structural information was presented, the team did show that the molecule had the ability to induce toxin production.

The final step involved determining whether TI was involved in infection. For this, the team acquired fecal matter from patients suffering from C. difficile infection and attempted to find the TI signal. It was most certainly there. In contrast, those not suffering from illness had no sign of the molecule. Although this was not a direct cause and effect link, the researchers were confident they had found the trigger.

By determining the mechanism behind toxin production, we now have a better understanding of how the bacterium turns from harmless microbe to killer infection. We also have a new potential target for antimicrobials. Unlike the use of antibiotics, which may lead to other problems, including resistance, this path may allow for direct targeting of the pathogen with little to no side effects. With new discoveries and eventual treatments, we may soon be able to deal with C. difficile to ensure anyone who becomes infected can recover fully and continue to enjoy his or her life.

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