Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

Abstract

Bitter and sweet taste G protein-coupled receptors (known as T2Rs and T1Rs, respectively) were originally identified in type II taste cells on the tongue, where they signal perception of bitter and sweet tastes, respectively. Over the past ~15 years, taste receptors have been identified in cells all over the body, demonstrating a more general chemosensory role beyond taste. Bitter and sweet taste receptors regulate gut epithelial function, pancreatic β cell secretion, thyroid hormone secretion, adipocyte function, and many other processes. Emerging data from a variety of tissues suggest that taste receptors are also used by mammalian cells to "eavesdrop" on bacterial communications. These receptors are activated by several quorum-sensing molecules, including acyl-homoserine lactones and quinolones from Gram-negative bacteria such as Pseudomonas aeruginosa, competence stimulating peptides from Streptococcus mutans, and D-amino acids from Staphylococcus aureus. Taste receptors are an arm of immune surveillance similar to Toll-like receptors and other pattern recognition receptors. Because they are activated by quorum-sensing molecules, taste receptors report information about microbial population density based on the chemical composition of the extracellular environment. This review summarizes current knowledge of bacterial activation of taste receptors and identifies important questions remaining in this field.

Keywords: Pseudomonas aeruginosa; Staphylococcus aureus; Streptococcus mutans; acyl-homoserine lactone; cilia; competence-stimulating peptide; gingival epithelial cells; nasal epithelium; quinolone; solitary chemosensory cell.

Figure 1

GPCR taste signal transduction pathway in a type II taste cell, as described in the text. Diagram created with BioRender.

Figure 2

Bitter compounds are structurally diverse. Shown are several structures of representative bitter compounds. An actively-maintained online database of bitter compounds (BitterDB [88]) contains over 1000 structurally diverse compounds shown to activate specific T2R isoforms in various cell models. Some bitter compounds exhibit a high degree of promiscuity among receptors (e.g., denatonium benzoate activates eight human T2Rs and quinine activates eleven T2Rs), while others are recognized by only one T2R (e.g., flufanamic acid activates T2R14 and phenylthiocarbamide (PTC) activates T2R38). An example of the structural diversity of compounds that can activate a single T2R is seen in the structures of diphenhydramine, aristolochic acid, quercetin, parthenolide, chloroquine, and lupulone, all of which can activate T2R14 [88,89]. In addition to small molecules, some proteins and peptides have also been shown to activate T2Rs [88]. This diversity can make predicting the “bitterness” or receptor specificity of specific bacterial metabolites very difficult without empirical testing. Bitter compounds shown were shown to activate the following human T2Rs in heterologous expression models [88,89]: denatonium benzoate, T2Rs4, 8, 10, 13, 39, 43, 46, 47; quinine, T2Rs4, 7, 10, 14, 39, 40, 43, 44, 46; diphenhydramine, T2Rs14, 40; flufenamic acid, T2R14; aristolochic acid, T2Rs14, 43; quercetin, T2R14; chloroquine, T2Rs3, 7, 10, 14, 39; phenylthiocarbamide, T2R38; andrographolide, T2Rs46, 47, 50; parthenolide, T2Rs1, 4, 8, 10, 14, 44, 46; caffeine, T2Rs7, 10, 14, 43, 46; yohimbine, T2Rs1, 4, 10, 38, 46; lupulone, T2Rs1, 14; amarogentin, T2Rs1, 4, 39, 43, 46, 47, 50.

Figure 3

Pseudomonas aeruginosa quorum-sensing molecules shown to activate T2Rs, as described in the text. Shown are N-3-oxo-dodecanoyl-L-Homoserine lactone (3oxoC12HSL), N-butyryl-L-Homoserine lactone (C4HSL), and 2-heptyl-3-hydroxy-4(1H)-Quinolone, also known as Pseudomonas quinolone signal (PQS).

Figure 4

Role of cilia-localized T2Rs in the innate immune response of the sinonasal cavity. Inhaled pathogens and debris are trapped in the mucus lining the mucosa [15]. Gram-negative bacteria, such as P. aeruginosa, produce bitter agonists of T2Rs expressed in the airway, including acyl-homoserine lactones (AHLs) and quinolones [160,161]. Activation of T2Rs by these bitter agonists induces the release of Ca²⁺ stores from the endoplasmic reticulum. The elevation of intracellular Ca²⁺ leads to the stimulation of nitric oxide (NO) production by the enzyme nitric oxide synthase (NOS). The NO produced and its reactive species can diffuse into the airway surface liquid (ASL) and have a direct killing effect on bacteria, and also possibly on viruses and fungi, by destroying their cell wall. Through activation of protein kinase G (PKG) and subsequent phosphorylation of various ciliary proteins, the NO produced also increases cilia beating frequency, which improves mucociliary clearance [15]. Diagram created with BioRender.

Figure 5

Macrophage T2R detection of bacterial AHLs or quinolones results in Ca²⁺-dependent NO production and enhancement of phagocytosis through protein kinase G [181,183,209]. Diagram created with BioRender.

Figure 6

Role of sweet (T1Rs) and bitter (T2Rs) taste GPCRs expressed in solitary chemosensory cells (SCCs) in human sinonasal innate immune response. (a) Under healthy conditions, the physiological concentration of glucose in the airway surface liquid (ASL) activates T1R2/3, resulting in the repression of T2R-mediated antimicrobial activity in the same SCC [74,134]. (b) During infection, a decrease of glucose levels outside the activation range of T1R2/3 (0.5–5 mM) leads to the inactivation of T1R2/3 and subsequent activation of T2R. This results in a Ca²⁺-dependent release of β-defensins 1 and 2, antimicrobial peptides that kill Gram-positive and Gram-negative bacteria, from surrounding epithelial cells [74,134]. Diagram created with BioRender.