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Bacteria and their different forms, movements and influences offer a seemingly unending number of research possibilities. In a recent study, researchers from the Georgia Institute of Technology have found that it is not true that bacterial collaborations within microbiomes, like in the mouth, have evolved to be generous and exclusive. In an interview with Dental Tribune International, Dr. Gina Lewin explains this in more detail and discusses other areas of the study.
Dr. Lewin, what was the main goal of the study?
There is a lot known about the microbes in the oral cavity: what microbes are there during health and disease, how the microbes are arranged in plaque and some details of how the microbes interact. To build on this knowledge base, we asked how universal the interactions are in the oral cavity and beyond. If a microbe Ainteracts a certain way with species B, will it also interact the same way with species C? And, further, we asked does it matter if species A and B are both from the oral cavity, where they have evolved in the same environment, versus species C that is from a different environment and does not regularly interact with oral microbes? Basically, by including both oral and nonoral microbes, we could ask how interactions differ between microbes that are native to the same environment and those that are not.
How did you arrive at your conclusions?
To perform this study, we focused on the microbe Aggregatibacter actinomycetemcomitans (Aa). We performed pairwise coinfections with Aa and 25 different microbes in an animal model, so each infection had Aa and one other microbe (and we infected with Aa alone as a comparison). We used sequencing techniques to ask how abundant each microbe was in the infection. This sequencing allowed us to identify that Aa was more fit in the presence of nonoral than oral microbes.
To characterize the genes that Aa needed to survive in the presence of the other microbes, we used a technique called transposon insertion sequencing (Tn-seq). Tn-seq is really powerful because it allows us to ask not what genes Aa uses the most but, specifically, which genes can it not survive without—its essential genome. To use this technique, we have a pool of Aa mutants where each individual cell in the pool has one gene disrupted by a small piece of DNA called a transposon. This disruption makes the gene nonfunctional. As we have about 100,000 cells in the pool and Aa has about 2,400 genes in its genome, we have a library where, across all the cells in the pool, each gene in the genome is disrupted multiple times. When we did the infections described, we injected this entire pool. If a gene is disrupted that is important for survival, that cell won’t be able to grow and divide, so that cell will decrease in relative abundance compared with the other cells in the pool. At the end of each experiment, we used sequencing to identify the locations of the transposons and count their abundance. Using computational analyses, I identified the genes that, when disrupted, made it impossible for Aa to survive. Then we asked how these genes change across all 26 conditions (monoinfection and 25 coinfections). Looking at how the essential genomes change told us how interactions with other microbes impact Aa.
So what exactly do these results tell us about bacterial collaborations?
These results tell us that these interactions—sometimes collaborations and sometimes competitions—are really complex. Tn-seq had never been used to study interactions before on the scale of this study. We identified that there is a small set of genes (59) that Aa always needs to survive and a much larger set of genes that Aa needs to survive in the presence of some microbes but not others. Many of the genes that Aa always needs to survive are involved in aerobic respiration, indicating that using oxygen is really important in the model environment that we used for these experiments, the murine abscess.
We also found that there are some interactions with oral microbes where Aa requires an especially large number of genes to be able to survive. This result indicates to us that the interactions with these oral microbes are extremely intricate and complex. Aa seems to be stressed by the presence of these other bacteria and requires a lot of genes to be able to acquire enough nutrients to survive. In contrast, there are a few nonoral microbes where Aa requires relatively few genes to survive. We hypothesize that these microbes provide additional nutrients to Aa, either directly or indirectly by changing the host environment.
How might the study help fight acute periodontitis?
Much of this work is honestly very basic science and steps away from direct relevance in the clinic. However, periodontitis is a challenging disease to treat partially because of the complex interactions between microbes in the oral microbial community. This work helps us better understand how interactions impact an acute periodontal pathogen.
In addition, the essential genes we identified in this study are necessary for survival. Therefore, researchers often look for essential genes when they want to design antibiotics to inhibit a pathogen. If you can inhibit the product of an essential gene, then the microbe cannot survive. While our study builds on previous work that shows that essential genes vary depending on the microbe present, we were also able to identify a set of genes that are always essential no matter the other microbe present. Potentially, these data could help with antibiotic design for fighting Aa in patients with acute periodontitis.
What will your next steps be in the research?
This work was fairly broad, so next we are interested in digging in and characterizing some of the interactions in this study in more detail. This future work will hopefully help us better understand the interactions between these microbes and why Aa’s essential genome changes.
In another direction, we are also interested in expanding to more complex communities. In this study, we only analyzed pairwise two-species communities, and we would like to build on what we learned in this study in order to understand interactions in more complex communities.
The study, titled “Large-scale identification of pathogen essential genes during coinfection with sympatric and allopatric microbes,” was published online on Sept. 24, 2019, in PNAS.
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