Host monitoring of quorum sensing during Pseudomonas aeruginosa infection

Spying on bacterial signals Many bacteria produce small molecules for monitoring population density and thus regulating their collective behavior, a process termed quorum sensing. Pathogens like Pseudomonas aeruginosa, which complicates cystic fibrosis disease, produce different quorum-sensing ligands at different stages of infection. Moura-Alves et al. used experiments in human cells, zebrafish, and mice to show that a host organism can eavesdrop on these bacterial conversations. A host sensor responds differentially to bacterial quorum-sensing molecules to activate or repress different response pathways. The ability to “listen in” on bacterial signaling provides the host with the capacity to fine-tune physiologically costly immune responses. Science, this issue p. eaaw1629 The host xenobiotic sensor quantitatively recognizes bacterial small molecules to regulate host responses. INTRODUCTION The interaction between a bacterial pathogen and its host can be viewed as an “arms race” in which each participant continuously responds to the evolving strategies of the other partner. A mechanism allowing bacteria to rapidly adapt to such changing circumstances is provided by density-dependent cell-to-cell communication known as quorum sensing (QS). QS involves a hierarchy of signaling molecules, which in pathogenic bacteria is associated with biofilm formation and virulence regulation. Notably, some QS molecules are detected by the host, and these can provoke specific immune responses. However, the receptors and their signaling pathways that the host uses to eavesdrop on bacteria remain poorly understood. RATIONALE We hypothesized that if a host sensor can detect and differentiate between bacterial QS molecules and their expression patterns, it will allow hosts to customize their immune responses according to the stage and state of infection. We recently showed that the aryl hydrocarbon receptor (AhR) directly recognizes pigmented bacterial virulence factors, such as the phenazines produced by Pseudomonas aeruginosa, which are downstream products of QS. Upon binding phenazines, the AhR elicits diverse immune responses that coordinate host resistance to infection. As a result of its capacity to sense a broad array of ligands, we postulated that the host AhR is well positioned to spy on bacterial communications, continuously monitor bacterial infection dynamics, and thereby signal to the host to tune immune responses according to the state of infection. RESULTS Our results demonstrated that infected hosts show differential modulation of host AhR signaling over the course of P. aeruginosa infection in zebrafish, mice, and human cells. AhR signaling depended on the relative abundances of several classes of P. aeruginosa QS molecules, including homoserine lactones (e.g., N-3-oxo-dodecanoyl-homoserine lactone), quinolones (e.g., 4-hydroxy-2-heptylquinoline), and phenazines (e.g., pyocyanin). In vitro and in vivo studies showed that the AhR not only detects P. aeruginosa QS molecules in a qualitative way but also quantifies their relative abundances. Quantitative assessment enables the host to sense bacterial community densities that may have distinct gene expression programs and infection dynamics, and thereby to regulate the scale and intensity of host defense mechanisms, which can range from induction of inflammatory mediators to immune cell recruitment and bacterial clearance. CONCLUSION Our findings emphasize a crucial role for host AhR as master regulator of host defense responses, capable of tuning immunity according to the stage of infection and disease. By inhibiting profuse and inessential immune responses, the host can counteract some of the detrimental effects of infection and avoid collateral damage. We propose that host surveillance of bacterial communication allows not only a trade-off between energy expenditure and efficient defense in the host, but also a trade-off between energy expenditure and virulence in the pathogen. QS is not restricted to P. aeruginosa, and we postulate that monitoring of bacterial QS by hosts may be a widespread phenomenon. Different therapeutic strategies to manipulate P. aeruginosa QS have been attempted, including adaptive treatment regimens for cystic fibrosis patients, who suffer severely from this pathogen. A better understanding of the cross-talk between host AhR and bacterial QS could pave the way to specific host-directed therapies to treat infectious diseases, tailored not only to the type of infection but also to the specific stage of disease. Bacterial communication under the radar of the host aryl hydrocarbon receptor (AhR). The AhR spies on bacterial communication and translates the bacterial signaling vocabulary into the most appropriate host defenses. The expression of bacterial quorum-sensing molecules, such as homoserine lactones, quinolones, and phenazines, varies according to community density and state of infection. The AhR can detect the type and quantity of quorum-sensing molecules and hence the state of infection, and thus tunes host defenses. Pseudomonas aeruginosa rapidly adapts to altered conditions by quorum sensing (QS), a communication system that it uses to collectively modify its behavior through the production, release, and detection of signaling molecules. QS molecules can also be sensed by hosts, although the respective receptors and signaling pathways are poorly understood. We describe a pattern of regulation in the host by the aryl hydrocarbon receptor (AhR) that is critically dependent on qualitative and quantitative sensing of P. aeruginosa quorum. QS molecules bind to AhR and distinctly modulate its activity. This is mirrored upon infection with P. aeruginosa collected from diverse growth stages and with QS mutants. We propose that by spying on bacterial quorum, AhR acts as a major sensor of infection dynamics, capable of orchestrating host defense according to the status quo of infection.