Signal Transduction Network Principles Underlying Bacterial Collective Behaviors

Abstract

Bacteria orchestrate collective behaviors and accomplish feats that would be unsuccessful if carried out by a lone bacterium. Processes undertaken by groups of bacteria include bioluminescence, biofilm formation, virulence factor production, and release of public goods that are shared by the community. Collective behaviors are controlled by signal transduction networks that integrate sensory information and transduce the information internally. Here, we discuss network features and mechanisms that, even in the face of dramatically changing environments, drive precise execution of bacterial group behaviors. We focus on representative quorum-sensing and second-messenger cyclic dimeric GMP (c-di-GMP) signal relays. We highlight ligand specificity versus sensitivity, how small-molecule ligands drive discrimination of kin versus nonkin, signal integration mechanisms, single-input sensory systems versus coincidence detectors, and tuning of input-output dynamics via feedback regulation. We summarize how different features of signal transduction systems allow groups of bacteria to successfully interpret and collectively react to dynamically changing environments.

Keywords: bacterial group behavior; c-di-GMP; feedback; quorum sensing; sensitivity; signal transduction; specificity.

Fig. 1.. Classes of receptors regulating bacterial group behaviors.

A) Small molecule binding transcription factors of the LuxR family function by detecting acyl homoserine lactones (AHLs). Liganded LuxR-type proteins control genes specifying group behaviors. LBD = ligand binding domain; DBD = DNA binding domain. B) Two-component systems function by phosphorylation/dephosphorylation cascades. The vibrio AI-2 SHK LuxPQ and its downstream signal-relay components are shown. LuxQ is a kinase at LCD and a phosphatase at HCD. HK = histidine kinase; REC = receiver domain. C) The second messenger c-di-GMP controls biofilm formation in many bacteria. The vibrio c-di-GMP regulatory polyamine NspS/MbaA receptor complex detects norspermidine (Nspd) and spermidine (Spd). When norspermidine is detected, MbaA produces c-di-GMP via its GGDEF domain. When spermidine is detected, MbaA degrades c-di-GMP via its EAL domain. MbaA-driven changes in c-di-GMP levels alter activity of downstream effectors which are transcription factors. See text for descriptions of all three types of systems. Figure created with BioRender.com.

Fig. 2.. Specificity in AHL quorum sensing.

(A) The A. baumannii AbaR receptor is activated by its cognate autoinducer with high specificity. Non-cognate AHLs produced by other bacteria commonly antagonize AbaR, restricting cells to the LCD gene expression mode even when the cognate ligand is abundant. (B) The P. aeruginosa LasR receptor exhibits relaxed specificity and activates the HCD quorum-sensing gene expression program when bound to its cognate ligand or to many AHLs produced by other bacteria. Only select AHLs antagonize LasR. (C) Although unrelated to LuxR-type receptors, the V. harveyi LuxN two-component SHK receptor recognizes an AHL ligand. LuxN is highly specific for its cognate autoinducer and is antagonized by other AHLs. AHLs that are similar in structure to the cognate ligand only partially antagonize LuxN, whereas highly divergent AHLs strongly antagonize its activity. Figure created with BioRender.com.

Fig. 3.. Features of the vibrio quorum-sensing circuit.

(A) Diagram of coincidence detection for a simplified quorum-sensing circuit containing only two receptors, LuxPQ and CqsS. (Left panel) When both receptors are unliganded, kinase activity drives LuxO phosphorylation and LCD behaviors are enacted. (Middle panel) When one receptor is unliganded, it functions as a kinase (in the scheme that is LuxPQ). The ligand-bound receptor functions as a phosphatase (in the scheme that is CqsS). Kinase activity overpowers phosphatase activity, and the cells remain in the LCD state. (Right panel) HCD behavior occurs only when both autoinducers are simultaneously detected, and thus the coincidence detection requirement is satisfied. (B) The V. cholerae biofilm lifecycle, when cells are grown in monoculture, over increasing cell densities. The genus specific CAI-1 autoinducer accumulates first, but biofilm dispersal does not occur until AI-2, which accumulates later in growth, stimulates the coincidence detector. (C) The V. cholerae biofilm lifecycle in a multi-species consortium containing other AI-2 producing bacteria. Endogenous CAI-1 combined with exogenous sources of AI-2 activate the coincidence detector at an early stage of biofilm formation leading to premature biofilm dispersal. Figure created with BioRender.com.

Fig. 4.. The Qrr sRNAs control quorum-sensing target genes.

The Qrr sRNAs function by four post-transcriptional regulatory mechanisms. They activate translation by facilitating ribosome binding. They repress translation by sequestration, coupled degradation, and catalytic degradation of target mRNAs. One representative target mRNA that is controlled by each mechanism is shown. Figure created with BioRender.com.

Fig. 5.. Autoregulatory feedback loops in the V. harveyi/V. cholerae quorum-sensing circuit.

Negative autoregulatory feedback loops are colored magenta and positive autoregulatory feedback loops are colored green. Two additional regulatory loops exist that control receptor levels, shown in blue. Figure created with BioRender.com.