Bacterial quorum sensing in complex and dynamically changing environments

Abstract

Quorum sensing is a process of bacterial cell-to-cell chemical communication that relies on the production, detection and response to extracellular signalling molecules called autoinducers. Quorum sensing allows groups of bacteria to synchronously alter behaviour in response to changes in the population density and species composition of the vicinal community. Quorum-sensing-mediated communication is now understood to be the norm in the bacterial world. Elegant research has defined quorum-sensing components and their interactions, for the most part, under ideal and highly controlled conditions. Indeed, these seminal studies laid the foundations for the field. In this Review, we highlight new findings concerning how bacteria deploy quorum sensing in realistic scenarios that mimic nature. We focus on how quorums are detected and how quorum sensing controls group behaviours in complex and dynamically changing environments such as multi-species bacterial communities, in the presence of flow, in 3D non-uniform biofilms and in hosts during infection.

Fig. 1 |. Quorum-sensing circuits.

Bacterial quorum sensing relies on networks of autoinducers, autoinducer synthases, partner autoinducer receptors and downstream signal transduction components that convert the information contained in autoinducers into changes in gene expression. a | When Vibrio spp. are at a low cell density, autoinducer levels are low, and their cognate receptors activate a phosphorylation cascade that ultimately results in the activation of the transcription factor AphA, which mediates individual behaviours. By contrast, at high cell density, the synthases LuxM, LuxS, CqsA and Tdh produce high levels of the autoinducers AI-1, AI-2, CAI-1 and DPO, respectively, and the corresponding receptors function as phosphatases. Instead of AphA, LuxR or HapR is produced, which ng loops using LasI and LasR, RhlI, PqsE andmediates group behaviours. b | Pseudomonas aeruginosa employs four interwoven quorum-sensi RhlR, PqsABCDH and PqsR, AmbBCDE and an unknown receptor as the synthases and receptors of the autoinducers 23OC12-HSL, C4-HSL, unknown (PqsE), PQS and IQS, respectively. c | At high cell densities, AgrB from Staphylococcus aureus processes the AgrD precursor peptide and exports the autoinducing peptide AIP, which in turn signals through the AgrC receptor and the downstream transcription factor AgrA. Phosphorylated AgrA induces the production of a regulatory RNA that controls group behaviours. sRNA, small RNA. Dashed lines represent phosphorylation and dephosphorylation. Solid lines represent gene regulation or protein production or small molecule production. Adapted with permission from REF., Elsevier.

Fig. 2 |. Fluid flow and surface topography influence quorum-sensing dynamics.

a | Bacterial populations can exhibit heterogeneous quorum-sensing activation patterns under different flow and topography regimes, ranging from quorum-sensing-off cells (red throughout the figure) to partially quorum-sensing-on cells (orange throughout the figure) and fully quorum-sensing-on cells (yellow throughout the figure). Flow (straight arrows for continuous flow and curvy arrows for periodic flow; arrows are pointing in the direction of flow throughout the figure) can wash away endogenously produced autoinducers unless the cells are shielded in a thick biofilm or in crypt-like niches. b | Quorum sensing is activated within thick biofilms of Staphylococcus aureus grown in a microfluidics channel (see Supplementary Movie 1). The left panel shows a 3D view and the right panel shows single optical sections of the x–y plane, 10 μm above the surface–biofilm interface, with z projections shown to the right (x–z plane) and below (y–z plane). The white arrow shows the flow direction. c | Under steady flow, the normalized quorum-sensing output is low in S. aureus compared with no-flow conditions during which autoinducers can accumulate and drive increased quorum-sensing output. Periodic flow leads to quorum-sensing responses that fluctuate between on and off and thus a stepwise increase in quorum-sensing output. d | In the left panel, fluorescent tracer beads flow into a corrugated microfluidics channel with crypt-like cavities, which are shielded from the surface flow and thus trap the beads. Similarly, S. aureus (middle) and Vibrio cholerae (right) growing in the cavities are shielded from flow and, thus, autoinducers can accumulate and turn on quorum sensing (see Supplementary Movie 2). a.u., arbitrary unit. Adapted with permission from REF, Springer Nature Limited.

Fig. 3 |. Heterogeneity in quorum sensing.

a | Pseudomonas putida can exhibit heterogeneous quorum-sensing responses, in particular, during the early stages of biofilm growth. Only some cells in growing microcolonies produce GFP from a plasmid carrying a quorum-sensing-dependent reporter fusion (lasB–gfp) and the autoinducer receptor. The construct thus reports on individual cell autoinducer production and autoinducer response. Thus, quorum-sensing-regulated putisolvin production occurs only in a subpopulation of cells, and those cells subsequently disperse from the clusters. The upper panel shows a close-up view of the region outlined in the lower panel, and green shows GFP production. The red arrows indicate a cell that leaves the microcolony (top far left; cell absent in middle and right top panels), and the white arrows indicate a cell that moves to the periphery of the microcolony. b | Such heterogeneity can be explained through the concept of quorum sensing as a bistable response function^,. The dashed line indicates the autoinducer threshold level. The curve shows the quorum-sensing response to different autoinducer (triangles) levels. To achieve bistability, autoinducer production is downregulated in cells that detect it below the threshold value and upregulated in cells that detect it above this threshold. At low cell density, the system is fixed in quorum-sensing-off mode (stable fixed point at 0), and the bacteria exhibit individual behaviours. At high cell density, the system is fixed in quorum-sensing-on mode (stable fixed point at 1), and the bacteria exhibit group behaviours. At intermediate levels (unstable fixed point), transitions between quorum-sensing-on or quorum-sensing-off modes are driven by fluctuations in autoinducer concentration. Part a is reproduced from REF, CC-BY-4.0.

Fig. 4 |. Quorum sensing and the public goods dilemma.

a | Chitin degradation represents a public goods dilemma. Chitinase producers (yellow in parts a–c) secrete chitinase enzymes (purple hexagons) that degrade the chitin polymer (light blue in parts a–c) into soluble N-acetylglucosamine oligomers (tan circles in part a), which can be imported and catabolized by both chitinase producers and chitinase nonproducers (red in parts a–c). b | In static liquid culture, Vibrio cholerae chitinase producers that compete against chitinase nonproducers on chitin make thick biofilms and outcompete the nonproducers. c | Similarly, chitinase nonproducers fail to accumulate biomass when soluble products of chitin degradation are washed away by flow (right), whereas they can exploit the public good in the absence of flow (left). d | Matrix production confers a competitive advantage to wild-type Pseudomonas aeruginosa (green) over a ΔpelA non-matrix producing mutant (red) in biofilms under flow conditions. The images show that wild-type bacteria contribute to the main biofilm biomass, while the ΔpelA mutant cells are excluded. e | The Pel-deficient P. aeruginosa mutant (red) can occupy locations protected from flow owing to local clogging by wild-type P. aeruginosa (green) biofilm streamers. White lines indicate bead tracks monitoring flow; yellow arrows highlight flow trajectories. Parts a–c are adapted with permission from REF., Elsevier. Parts d–e are adapted from REF., CC-BY-4.0.

Fig. 5 |. Quorum sensing and the host microbiota.

a | Quorum sensing can control the species composition of the gut microbiota. Disruption of the normal microbiota composition by antibiotic treatment leads to a reduction in AI-2-producing bacteria (and AI-2 levels), resulting in dysbiosis. In this instance, members of the Firmicutes phylum (green) are the primary AI-2 producers, and their abundance decreases following antibiotic treatment, while members of the Bacteroidetes phylum (blue) increase in abundance. However, artificially increasing AI-2 levels by introduction of an AI-2 producer (in this case, an engineered strain of Escherichia coli) partially restores the normal gut microbiota composition. b | The gut commensal bacterium Blautia obeum can produce the DPO autoinducer, and DPO is speculated to inhibit colonization by Vibrio cholerae, possibly providing protection against this pathogen^,. c | Communication can also occur between mammalian epithelial cells and bacteria. Epithelial cells release an AI-2 mimic in response to bacteria, and this AI-2 mimic is detected by bacterial colonizers via their AI-2 quorum-sensing receptors. Thus, the AI-2 mimic modulates bacterial quorum sensing.

Fig. 6 |. Host factors influence quorum sensing.

Host-derived enzymes and other proteins can modulate bacterial quorum sensing by altering autoinducer levels through processes including autoinducer modification (part a), autoinducer degradation (part b) or autoinducer sequestration^, (part c). These processes, because they inactivate autoinducers (parts a, b) or make autoinducers unavailable (part c), induce the LCD quorum-sensing state, causing bacteria to enact individual behaviours.