I recently read an article published in the Public Library of Science (link) about biofilm development on nematodes. Before getting into the article, some background is needed.
Bacteria are classically seen as unicellular organisms that exist independently of one another. These cells do not communicate with each other, and are really just a large group of individuals. Cell in multicellular organisms, in contrast, communicate with each other extensively through a variety of means. There are individuals, but individuals exist for the good of the whole. (Cancer is an example of individuals acting in the interest of individuals, as opposed to acting in the interest of the whole organism.)
This model is nice and simple, but untrue. Different species and strains of bacteria show certain levels of communication. Though none of these forms of communication are as extensive as those seen in multicellular organisms, they are still significant. A fairly common type of bacterial communication is known as quorum sensing. In quorum sensing, bacterial cells are able to send a message to each other that essentially reads "we have reached a certain size".
As to how bacteria respond to this message depends on the particular species. For certain pathogenic bacteria, it is interpreted as an attack message. For a small group of bacteria, attacking a host would be certain death. The numbers are too small to cause significant damage to the host, minimizing the amount of gain from an attack. More importantly, the host will mount defenses in the form of an immune response, and a small group could very quickly be eradicated. For a small group, it is much more advantageous to sit and wait. The groups numbers slowly build, but the bacteria are proverbially under the radar of the host. As long as the bacteria are not actually harming the host, the host has no advantage in expending energy and attacking the bacteria. At some point, the bacterial numbers become significant, to the point where an immune response would not be able to dispatch the bacteria so quickly. It is at this point where the size signal is sent, triggering the bacteria to attack the host. Such behavior is quite advantageous, showing the power of such a seemingly simple signal.
In the paper, the authors looked at biofilm development of a certain group of bacterium, namely Yersinia. (Yersinia includes the infamous Yersinia pestis, which causes the black plague.) Biofilms are the closest bacteria get to being multicellular. Within a biofilm, bacteria live in close quarters with each other, producing a variety of compounds that benefit the group as a whole. Biofilms act as a platform for growth, and as a whole tend to be resistant to things that would otherwise kill off bacteria, including antibiotics. The creation of biofilms is no simple feat for bacteria, and it is often mediated by the production of chemical signals to each other.
Enter the poor nematode. This is a simple, very tiny worm, which is often used as a model organism in biology. Yersinia can actually make its home on nematodes, and is even capable of making biofilms on nematodes. The authors investigated how such biofilms were made. Given that the nematodes are capable of (and do) move around, such biofilms seem to be an interesting area of study, as many biofilms tend to develop on static surfaces. Sure enough, the construction of these motile biofilms is mediated by the same quorum sensing signals as seen in other bacteria. Biofilms are loaded with the quarum sensing signal, namely N-acylhomoserine lactone (AHL). The authors genetically engineered bacteria that were incapable of making AHL, and the resulting bacteria were unable to develop substantial biofilms. In addition to biofilm production, they also found that quorum sensing signals triggered pathogenesis in general, as evidenced by the need for AHLs to make virulon proteins.
Though quorum sensing appears to be widely utilized by bacteria, there appears to be a large amount of variation on the common theme. There are a lot of different ways in which a "we number this many" signal can be used advantageously for bacteria. Life, through evolution, tends to explore many of niches, and experimentally it seems that quorum sensing is no exception. The authors note how a number of other pathogens utilize quorum sensing in their own specific ways.
This leads to an interesting topic for experimental drugs. Without the quorum sensing signal, certain pathogens never actually express pathogenic behavior. If we can develop a drug that prevents this signal from ever reaching its target, be it through destroying the signal, blocking its receptor, or some other means, then the bacteria in question never mount an attack. While they are still there, they are effectively harmless. It seems that quorum sensing is specific to bacteria, so presumably such drugs would target bacteria specifically. Additionally, being that quorum sensing is a common theme for pathogens, such drugs may specifically target pathogenic bacteria, sparing "good" bacteria. This is unlike modern broad spectrum antibiotics, which usually kill off everything. (Many of the negative side effects of antibiotics are due to good bacteria getting killed.) There seems to be a lot of good that could come of quorum sensing research, and I'm excited to see what the future holds for it in terms of medicine.
It seems that all these developing alternate routes to eradicate infections and tumors, such as targeting quorum sensing mechanisms and monoclonal antibody therapies, are all on the cusp of being very successful on a large-scale basis. I wish they were ready to leave clinical trials and become routine treatments.
ReplyDeleteDitto. Though from what I remember from Dr. Savka, they've been having problems with utilizing it. As of a few years ago, they hadn't yet developed an effective strategy for destroying or blocking AHLs. They did come up with ways to make AHL mimics that would trigger the same effects as normal AHLs. The idea was that if the bacteria got the attack signal too early the plant would have a better chance. It did reduce plant damage, but yields were still substantially lower.
ReplyDeleteHopefully things have improved since then. I haven't kept up with it.
Kyle, this was an extremely helpful blog. I was not able to write one this past week as I thought I understood this article. It turns out, the more I read it, the less I understood.
ReplyDeleteSo if there are drugs to prevent quorum sensing signals from being released or received, would this drugs have to be taken before you are even aware that you have the disease? At that point, isn't the biofilm formed and releasing escape pods of bacteria? So wouldn't they develop a resistance just like bacteria have started to with antibiotics?
I oversimplified it a bit when I said "attack" signal. It's more like a "attack and keep attacking" signal. So if you can stop the signal even after the biofilm is established, the biofilm will not be maintained and will soon break down.
ReplyDeleteIn the case of a mimic agonist, you would have to take it beforehand like you said. But for something that can actually destroy the signal, you can take it after infection has occurred.
As for resistance, it's theoretically possible, but not as strong. It all depends on how exactly the signal is being disrupted. With something that binds to the signal receptor, chances are likely low for resistance development. If a new receptor comes about that the drug doesn't bind to, chances are good that it won't bind to the regular signal either. If it can't bind the regular signal, then the bacterium looses the ability to communicate, defeating the purpose of the system. In other words, mutations that lead to drug resistance would more than likely cause the same effect as the drug. For similar reasons, bacteria rarely develop resistance to bacteriophages, because resistance is usually at the steep cost of something else.