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Communication Motifs: Principles of bacterial communication in non-genetically diversified populations

Final Report Summary - COMMOTS (Communication Motifs: Principles of bacterial communication in non-genetically diversified populations)

Bacteria communicate by the exchange of signaling molecules to coordinate their behavior, often to synchronize a homogenous population response. On the other hand, under stress conditions they diversify their phenotypes. The role of bacterial signaling in this process is poorly understood. In this project we established an innovative research methodology based on advanced fluorescence microscopy, molecular microbiology and mathematical modeling to address this question.

We developed a long-term correlative time-lapse microscopy assay to monitor the self-organization of B. subtilis in response to nutrient-fluctuations in unprecedented detail. We discovered that the heterochronous sporulation of B. subtilis under starvation stress results in the formation of subpopulations of spores with different revival properties and showed that this process is coordinated by a bacterial communication system. By a combination of theory and experiments, we elucidated the molecular mechanisms that gives rise to differential spore properties and found that it is at least in part due to a phenotypic memory of the cellular growth and gene expression history prior to sporulation. This phenotypic memory can give rise a spore quality versus quantity trade-off that can be modulated by cell-to-cell signaling.

In a second line of research we elucidated structure-function relationships in bacterial communication networks. To this end, we parsed the network into functional modules and network motifs that capture the different levels required for bacterial communication. We analyzed how different signaling architectures differ in their way of encoding information about cell density into a concentration of signaling molecules, how the allosteric properties of the signaling receptor affect how this information is processed and transduced to the response regulator and finally, how this information is decoded on the level of the promoter to regulate target gene expression.

With the help of various fluorescent reporter systems constructed in this project, including a novel FRET-reporter, we studied these processes experimentally. Notably, we discovered and experimentally characterized a number of new regulatory elements in signaling networks of bacteria and revealed an unexpected complexity of transcription regulation by the communication master regulator ComA in B. subtilis.

Overall, these studies have helped to refine our understanding of the organization of bacterial communication networks and how this relates to their physiological function. Moreover, with the help of our theoretical models we systematically explored how alternative designs affect the behavior of the network. Thereby, in the spirit of synthetic biology, we build a theoretical foundation to facilitate forward-engineering of tailored molecular components and cellular communication networks, respectively.

Together our studies advance our understanding of how communication controls complex adaptive behaviors in bacteria. The organizing principles that are derived from our studies should help to control bacterial populations in biotechnological settings and facilitate molecular level engineering to implement desired collective functionalities into synthetic microbial consortia in the future.