A Model for Phage Communication and the Implications for the Human Microbiome

The research group prepared
two types of media to test phage
infection efficacy.

Well we took a bit of a break these past couple of weeks, but we are back for the new year! Welcome to the Prophage blog 2017! The year has actually been off to a good start, with a lot of interesting papers being published this January. This week I want to kick things off by covering a very cool 2017 study by Erez et al that described an new and interesting mechanism by which bacteriophages communicate using their bacterial hosts. This really is a well written and elegant study that I highly suggest you read. In this post, I want us to cover the highlights of the study, and then discuss what this will mean for future research endeavors.

The research group led by Erez et al began their work by testing the hypothesis that "bacteria secrete communication molecules to alert other bacteria of phage infection", but what they ended up finding was arguably much more interesting. They began their series of experiments by simply growing bacteria in liquid media with and without bacteriophages (see the figure to the right). They let the mixture sit long enough for the phages to infect their bacterial hosts for a couple of replication cycles (3 hours), and then removed all of the bacteria and phages from the liquid by filtration. At this point, if there was a signaling molecule released during the infection, it would still be in the media even though the phages and bacteria were removed. Additionally, if there was a signaling molecule released during the phage infection period, repeating an infection in that same media would result in altered growth patterns (for example, less bacteria killed when the molecule is present). As it turns out, this is exactly what they observed.

The group found that phage infections were much less efficient when done in media that had already been used for phage infections. After careful study, the researchers found that the signaling molecule was in fact a small protein that was associated with the phage, not the bacterial host. The signal was highly phage specific. This meant that their observation was not of bacterial warning as initially hypothesized, but rather phage signaling to other phages. This is the first time such an extracellular signaling mechanism has been described between phages (at least as far as I know), which is pretty significant.

Following further characterization, the group found that the protein is (could be) used by many different phages to signal to other of the same phages whether they should enter a lytic replication cycle (reproduce and kill the bacterial host) or a lysogenic cycle (integrate into the bacterial genome and exist silently). The authors end their paper with a proposed mechanistic model for the phage to phage communication. They call this system the arbitrium system, after the latin word for decision.

The authors propose this mechanistic model for phage signaling.

What really makes this study cool is the implications it could have for microbiology and associated clinical applications. I think this finding could be especially important for our understanding of the human microbiome and virome. As we study the microbiome we strive, in part, to understand how bacteria and phages interact in human systems such as the gut, and understanding phage to phage signaling will be important for obtaining a more accurate picture of the system.

These findings could lead to some very interesting experiments. How would a cocktail of this type of signaling molecule (the authors identify many) alter gut virus or bacterial communities? How would this impact microbiome stability? Would a decrease in phage lytic capabilities significantly disrupt the kill-the-winner dynamics we see in the human microbiome, and result in low bacterial diversity with some un-checked bacteria taking over? The human microbiome is a complicated system, but this could be a step toward better understanding its dynamics, and maybe even contribute toward therapeutic applications.

I also think that these findings could be important for phage engineering and phage therapy. One of the big challenges in phage therapy is obtaining lytic bacteriophages that can effectively kill the pathogenic bacterial target. Lysogenic phages can also be effective in phage therapy, although they may be more effective if lysogeny could be avoided. It may also be advantageous to knock this gene out of phage therapy candidates.

In the end, this study has a lot of implications and I bet microbiologists are already thinking of hundreds of experiments they can conduct. And that is really what makes this study cool. It not only offers important information to the field, but it really captures and inspires the imagination of other scientists who read it. So if you have not read it yet, I highly suggest you go check it out.

What were your thoughts about the study? What implications do you think this will have for microbiology and the human microbiome? Let us know in the comments section, along with all of your questions, comments, and concerns. You can always reach out by Twitter or email as well.

References

Erez, Z., Steinberger-Levy, I., Shamir, M., Doron, S., Stokar-Avihail, A., Peleg, Y., Melamed, S., Leavitt, A., Savidor, A., Albeck, S., Amitai, G., & Sorek, R. (2017). Communication between viruses guides lysis–lysogeny decisions Nature, 541 (7638), 488-493 DOI: 10.1038/nature21049