Quorum Sensing Desynchronization Leads to Bimodality and Patterned Behaviors

Quorum Sensing (QS) drives coordinated phenotypic outcomes among bacterial populations. Its role in mediating infectious disease has led to the elucidation of numerous autoinducers and their corresponding QS signaling pathways. Among them, the Lsr (LuxS-regulated) QS system is conserved in scores of bacteria, and its signal molecule, autoinducer-2 (AI-2), is synthesized as a product of 1-carbon metabolism. Lsr signal transduction processes, therefore, may help organize population scale activities in numerous bacterial consortia. Conceptions of how Lsr QS organizes population scale behaviors remain limited, however. Using mathematical simulations, we examined how desynchronized Lsr QS activation, arising from cell-to-cell population heterogeneity, could lead to bimodal Lsr signaling and fractional activation. This has been previously observed experimentally. Governing these processes are an asynchronous AI-2 uptake, where positive intracellular feedback in Lsr expression is combined with negative feedback between cells. The resulting activation patterns differ from that of the more widely studied LuxIR system, the topology of which consists of only positive feedback. To elucidate differences, both QS systems were simulated in 2D, where cell populations grow and signal each other via traditional growth and diffusion equations. Our results demonstrate that the LuxIR QS system produces an ‘outward wave’ of autoinduction, and the Lsr QS system yields dispersed autoinduction from spatially-localized secretion and uptake profiles. In both cases, our simulations mirror previously demonstrated experimental results. As a whole, these models inform QS observations and synthetic biology designs.Author Summary: Bacterial behavior is responsive to a multitude of soluble molecular cues. Among them are self-secreted autoinducers that control quorum sensing (QS) processes. While new quorum sensing systems are constantly being discovered, several systems have been well defined in terms of their molecular and genetic topologies, each influencing a variety of resultant phenotypes. These quorum sensing systems include LuxIR homologs that use an array of species specific autoinducers and Lsr system homologs that share a single autoinducer among numerous species. Here we suggest that the regulatory topology of these two systems mark them as opposites of a sort. Whereas the LuxIR system bears a strong positive intercellular feedback mechanism, the Lsr system bears strong negative intercellular feedback. In our simulations these differences are manifested in distinct patterns of signaling. This was readily visualized in the outward spread of autogenous LuxIR expression in a growing bacterial 2D ‘colony’ whereas a dispersed activity was produced by autogenous Lsr expression in an otherwise identical colony. Here, this dispersed activity is a reflection of bimodal Lsr expression. We show that this bimodality could arise from desynchronized Lsr driven autoinducer import (intercellular negative feedback). This may have consequences on the arrangement of downstream phenotypes.