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Bacteria and fungi ubiquitously coexist, with their interactions critically influencing human health and industrial processes. Quorum sensing (QS) is a core regulatory mechanism that enables density-dependent coordination and phenotypic responses across these two kingdoms. While bacteria and fungi utilize their respective QS systems to engage in competitive or cooperative interactions to enhance their environmental adaptability, the current understanding of QS-based communications between them remains scattered, and a systematic summary of this field is still lacking. In this review, we examine the intricate dialog between bacteria and fungi, focusing on its role in microbial network assembly and ecosystem function, to provide a comprehensive analysis and engineering perspective on QS-based cross-kingdom communication. Specifically, we will first briefly delineate the core architecture of bacterial and fungal QS systems and the phenotypes they govern. Then, we will analyze QS-based interactions across diverse environments between different bacteria and fungi, categorizing natural QS interactions based on various phenotypes, including biofilm co-assembly and metabolic complementation. We further compare and analyze synthetic biology strategies, including promoter engineering and directed evolution of QS regulatory components, for reprogramming bacterial-fungal interactions and their applications. By synthesizing and contrasting these natural paradigms with synthetic designs, we provide a blueprint for achieving modular control over bacterial-fungal communities in diverse environments. Finally, by outlining persistent challenges and future trends, we aim to propel this field forward, enabling the deciphering of complex microbial interactions and ultimately increasing our capacity to engineer microbial consortia for diverse applications.

SmcR family proteins were discovered in the 1990s as central regulators of quorum-sensing gene expression and later discovered to be conserved in all studied Vibrio species. SmcR homologs regulate a wide range of genes involved in pathogenesis, including but not limited to genes involved in biofilm production and toxin secretion. As archetypal members of the broad class of TetR-type transcription factors, each SmcR-type protein has a predicted ligand-binding pocket. However, no native ligand has been identified for these proteins that control their function as regulators. Here, we used SmcR-specific chemical inhibitors to determine that ligand binding drives proteolytic degradation in vivo , providing the first demonstration of SmcR function connected to ligand binding for this historical protein family.

Quorum sensing (QS) enables bacteria such as Pseudomonas aeruginosa to coordinate cooperative activities. How bacteria in cooperating groups can resist infiltration by non-cooperating variants is an emerging area of interest in sociobiology and molecular biology. There have been several recent reports on how QS and certain bacteriophage interact. In some strains of P. aeruginosa , QS can activate phage defense systems. At least one bacteriophage can repress P. aeruginosa QS. Here, we show that a previously undescribed bacteriophage can help cooperating groups of P. aeruginosa resist infiltration by non-cooperating QS mutants. This represents a mutualism in which both the bacteriophage and the P. aeruginosa host benefit at least under certain conditions.

The discovery of quorum-sensing responsive linear plasmid phages has transformed understanding of phage-bacterial interactions by demonstrating inter-domain chemical communication. To date, however, examples of quorum-sensing responsive phages have been sparse. The founding example of such a phage, φVP882, detects a chemical communication signal molecule called DPO that is produced by diverse bacterial species. We investigated whether a family of VP882-like phages might exist that detect and respond to DPO. We find that indeed, VP882-like phages reside in DPO-producing bacterial species isolated at different times and geographic locations, suggesting their wide circulation in the environment. This discovery strengthens the evidence for the generality of phage-bacterial inter-domain chemical communication.

Bacteria release and sense small molecules called autoinducers in a process known as quorum sensing. The prevailing interpretation of quorum sensing is that by sensing autoinducer concentrations, bacteria estimate population density to regulate the expression of functions that are only beneficial when carried out by a sufficiently large number of cells. However, a major challenge to this interpretation is that the concentration of autoinducers strongly depends on the environment, often rendering autoinducer-based estimates of cell density unreliable. Here we propose an alternative interpretation of quorum sensing, where bacteria, by releasing and sensing autoinducers, harness social interactions to sense the environment as a collective. Using a computational model we show that this functionality can explain the evolution of quorum sensing and arises from individuals improving their estimation accuracy by pooling many imperfect estimates – analogous to the ‘wisdom of the crowds’ in decision theory. Importantly, our model reconciles the observed dependence of quorum sensing on both population density and the environment and explains why several quorum sensing systems regulate the production of private goods. Bacteria release and respond to autoinducers in a process known as quorum sensing. While classically viewed as a strategy to coordinate cell behaviour, Moreno-Gámez et al. demonstrate using modelling that quorum sensing may also be used to sense the environment as a collective by pooling information at relevant scales and harnessing the wisdom of the crowds.

The opportunistic pathogen Pseudomonas aeruginosa uses a cell-cell communication system termed \"quorum sensing\" to control production of public goods, extracellular products that can be used by any community member. Not all individuals respond to quorum-sensing signals and synthesize public goods. Such social cheaters enjoy the benefits of the products secreted by cooperators. There are some P. aeruginosa cellular enzymes controlled by quorum sensing, and we show that quorum sensing—controlled expression of such private goods can put a metabolic constraint on social cheating and prevent a tragedy of the commons. Metabolic constraint of social cheating provides an explanation for private-goods regulation by a cooperative system and has general implications for population biology, infection control, and stabilization of quorum-sensing circuits in synthetic biology.

Social interactions substantially influence the dynamics and functions of microbial communities. Cooperative behaviors serve to benefit populations, yet they are often exploited by cheating cells, thus creating a conflict between individuals in the microbial population. However, the underlying mechanisms by which cooperative behaviors are stabilized are incompletely elucidated. Here, we used quorum sensing (QS) as a model of cooperation, and functionally studied QS regulator LasR variant strains in the context of cooperative behaviors. We found that a LasR228 variant strain, bearing a non-conserved substitution in LasR, exhibited minimal LasR-dependent phenotypes. However, the function of this LasR228 variant strain was restored by inactivation of the transcriptional repressor PsdR, and the phenotypes of this variant strain were similar to the parental strain. Furthermore, we illustrate a post-transcriptional regulatory mechanism responsible for the activation of the LasR228 variant. Unlike LasR228, the PsdR-null-LasR228 strain demonstrated cooperative behaviors in competition with the LasR-null strain. Since psdR mutations precede the emergence of LasR variants in the evolution of P. aeruginosa using casein broth, this PsdR-mediated cooperative mechanism serves as an anticipatory control against potential cheating LasR variant strains. Additionally, our cell-killing assay showed that the cooperative PsdR-null-LasR228 strain was associated with increased bacterial pathogenicity to eukaryotic host cells. In conclusion, our study reveals the functional plasticity of LasR variants, which can be modulated by secondary mutations, affecting cooperation and conflict within populations. Our identification of a novel cooperative molecular mechanism offers insight into the maintenance of cooperation within microbial communities.

It has been argued that bacteria communicate using small diffusible signal molecules to coordinate, among other things, the production of factors that are secreted outside of the cells in a process known as quorum sensing (QS). The underlying assumption made to explain QS is that the secretion of these extracellular factors is more beneficial at higher cell densities. However, this fundamental assumption has never been tested experimentally. Here, we directly test this by independently manipulating population density and the induction and response to the QS signal, using the opportunistic pathogen Pseudomonas aeruginosa as a model organism. We found that the benefit of QS was relatively greater at higher population densities, and that this was because of more efficient use of QS-dependent extracellular \"public goods.\" In contrast, the benefit of producing \"private goods,\" which are retained within the cell, does not vary with cell density. Overall, these results support the idea that QS is used to coordinate the switching on of social behaviors at high densities when such behaviors are more efficient and will provide the greatest benefit.

Bacteria can be highly social, controlling collective behaviors via cell-cell communication mechanisms known as quorum sensing (QS). QS is now a large research field, yet a basic question remains unanswered: what is the environmental resolution of QS? The notion of a threshold, or “quorum,” separating coordinated ON and OFF states is a central dogma in QS, but recent studies have shown heterogeneous responses at a single cell scale. Quorum sensing (QS) is a mechanism of cell-cell communication that connects gene expression to environmental conditions (e.g., cell density) in many bacterial species, mediated by diffusible signal molecules. Current functional studies focus on qualitatively distinct QS ON/OFF states. In the context of density sensing, this view led to the adoption of a “quorum” analogy in which populations sense when they are above a sufficient density (i.e., “quorate”) to efficiently turn on cooperative behaviors. This framework overlooks the potential for intermediate, graded responses to shifts in the environment. In this study, we tracked QS-regulated protease ( lasB ) expression and showed that Pseudomonas aeruginosa can deliver a graded behavioral response to fine-scale variation in population density, on both the population and single-cell scales. On the population scale, we saw a graded response to variation in population density (controlled by culture carrying capacity). On the single-cell scale, we saw significant bimodality at higher densities, with separate OFF and ON subpopulations that responded differentially to changes in density: a static OFF population of cells and increasing intensity of expression among the ON population of cells. Together, these results indicate that QS can tune gene expression to graded environmental change, with no critical cell mass or “quorum” at which behavioral responses are activated on either the individual-cell or population scale. In an infection context, our results indicate there is not a hard threshold separating a quorate “attack” mode from a subquorate “stealth” mode. IMPORTANCE Bacteria can be highly social, controlling collective behaviors via cell-cell communication mechanisms known as quorum sensing (QS). QS is now a large research field, yet a basic question remains unanswered: what is the environmental resolution of QS? The notion of a threshold, or “quorum,” separating coordinated ON and OFF states is a central dogma in QS, but recent studies have shown heterogeneous responses at a single cell scale. Using Pseudomonas aeruginosa , we showed that populations generate graded responses to environmental variation through shifts in the proportion of cells responding and the intensity of responses. In an infection context, our results indicate that there is not a hard threshold separating a quorate “attack” mode and a subquorate “stealth” mode.

Many bacteria use a cell-cell communication system called quorum sensing to coordinate population density-dependent changes in behavior. Quorum sensing involves production of and response to diffusible or secreted signals, which can vary substantially across different types of bacteria. In many species, quorum sensing modulates virulence functions and is important for pathogenesis. Over the past half-century, there has been a significant accumulation of knowledge of the molecular mechanisms, signal structures, gene regulons, and behavioral responses associated with quorum-sensing systems in diverse bacteria. More recent studies have focused on understanding quorum sensing in the context of bacterial sociality. Studies of the role of quorum sensing in cooperative and competitive microbial interactions have revealed how quorum sensing coordinates interactions both within a species and between species. Such studies of quorum sensing as a social behavior have relied on the development of “synthetic ecological” models that use nonclonal bacterial populations. In this review, we discuss some of these models and recent advances in understanding how microbes might interact with one another using quorum sensing. The knowledge gained from these lines of investigation has the potential to guide studies of microbial sociality in natural settings and the design of new medicines and therapies to treat bacterial infections.