A role for airway taste receptor modulation in the treatment of upper respiratory infections

Abstract

Taste receptors, initially identified in the oral epithelium, have since been shown to be widely distributed, being found in the upper and lower respiratory tracts, gastrointestinal epithelium, thyroid, and brain. The presence of taste receptors in the nasal epithelium has led to the discovery of their role in innate immunity, defending the paranasal sinuses against pathogens. This article addresses the current paradigm for understanding the role of extraoral taste receptors, specifically the T2R38 bitter taste receptor and the T1R2+3 sweet taste receptor, in respiratory innate defenses and presents evidence for the use of these and other taste receptors as therapeutic targets in the management of chronic rhinosinusitis. Future studies should focus on understanding the polymorphisms of taste receptors beyond T2R38 to fully elucidate their potential therapeutic use and lay the groundwork for their modulation in a clinical setting to decrease the health impact and economic burden of upper respiratory disease.

Keywords: Airway physiology; TAS2R; chronic rhinosinusitis; epithelial biology; host-pathogen interactions; innate immunity; taste receptors; upper respiratory disease.

Figure 1. Umami, sweet, and bitter receptors

The receptors for umami (savory), sweet, and bitter are dimers of two G protein-coupled receptors. The umami and sweet receptors are heterodimers formed by T1R3 plus T1R1 or T1R2, respectively. In contrast to those receptors, there are 25 unique human bitter taste receptor genes or T2Rs, which function as monomers, or homodimers and heterodimers although the function of dimerization is uncertain.

Figure 2. Genomic organization and diversity of the TAS2R gene family

TAS2R genes, known collectively as the “bitterome,” are found on chromosomes 5, 7, and 12. Single nucleotide polymorphisms (SNPs) within the TAS2R loci exhibit significant individual variability, and are present as homozygous for the more common allele (black), homozygous for the less common allele (light grey), or heterozygeous (dark grey). SNPs unidentifiable for a subject are indicated in white. Each column represents a unique SNP; data from individual patients are organized by row.

Figure 3. Canonical type II taste receptor cell signaling

On stimulation with taste receptor agonists, the G-protein subunits Gα-gustducin and Gβγ dissociate from the G-protein coupled receptor. Subsequently, Gα-gustducin activates phosphodiesterase (PDE), which depletes cyclic adenosine monophosphate (cAMP) by converting it into adenosine monophosphate (AMP). Under normal conditions, the presence of cAMP activates protein kinase A (PKA), which inhibits several elements of the parallel Gβγ-mediated pathway. When released, Gβγ triggers phospholipase Cβ2 (PLCβ2), which produces inositol 1,4,5-trisphosphate (IP₃) from the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP₂). Once produced, IP₃ activates the type 3 IP₃ receptor (IP₃R3) on the endoplasmic reticulum, releasing calcium stores. Increased intracellular calcium opens the nonspecific cation channel TRPM5 (transient receptor potential cation channel subfamily M member 5), further depolarizing the cell and resulting in transmitter release.

Figure 4. Ciliated cells and solitary chemosensory cells (SCCs) express taste-related proteins

A: Explant of human nasal epithelium immunoreactive for bitter taste receptor T2R38 and the cilium marker β-tubulin IV. B: Air-liquid interface culture of nasal epithelium from a transgenic mouse co-expressing green fluorescent protein (GFP) with TRPM5 allows for the identification of SCCs. SCCs are also immunoreactive for the taste transduction protein α-gustducin.

Figure 5. Model of taste receptor signaling in the respiratory epithelium

Under healthy conditions, glucose present in the airway activates the sweet receptor dimer T1R2+3, silencing solitary chemosensory cells (SCCs). In the case of bacterial infection, this glucose is metabolized by the growing bacteria, which also release bitter compounds including acylhomoserine lactones (AHLs). Bitter bacterial metabolites activate T2Rs on SCCs and trigger an intracellular signaling cascade similar to canonical taste receptor cell signaling, including phospholipase Cβ2 (PLCβ2). In the mouse (dashed circle), this signaling cascade results in the release of acetylcholine (ACh) and activation of free trigeminal nerve fibers triggering neurogenic inflammation, mast cell degranulation, and an apneic reflex. In human primary cell cultures, activation of SCCs triggers a calcium wave via gap junctions to the surrounding epithelial cells stimulating the release of antimicrobial peptides from these cells, which is presumed to halt the growing bacterial infection. Furthermore, in humans, AHLs stimulate T2R38 on ciliated cells, which results in the activation of nitric oxide synthase (NOS) and the production of nitric oxide (NO). The production of NO increases ciliary beat frequency and thus accelerates mucociliary clearance. Additionally, NO diffuses into the mucus and airway where it is directly bactericidal.