Bitter Taste Receptors in Bacterial Infections and Innate Immunity

Abstract

Background: Bitter taste receptors (TAS2Rs), originally identified for their role in gustation, are now recognized for their functions in extraoral tissues, particularly in innate immune responses. TAS2Rs detect bacterial quorum sensing molecules (QSMs) and other metabolites, enabling the host to sense and respond to pathogenic threats across mucosal surfaces.

Objective: This review synthesizes current knowledge of TAS2Rs in the context of bacterial infection, emphasizing their mechanisms of immune modulation, genetic polymorphisms, tissue-specific expression, and therapeutic potential.

Methods: A comprehensive literature review was conducted, incorporating in vitro, ex vivo, and in vivo studies investigating TAS2R expression, signaling pathways, and immune functions in response to bacterial pathogens across respiratory, gastrointestinal, and oral tissues.

Results: TAS2Rs detect bacterial QSMs, triggering calcium signaling cascades, nitric oxide (NO) release, antimicrobial peptide secretion, and cytokine responses. In respiratory epithelium, TAS2R38 and TAS2R14 modulate mucociliary clearance and NO-mediated bacterial killing. In the oral cavity, TAS2R14 and TAS2R38 influence cytokine production, bacterial uptake, and antimicrobial responses. Intestinal TAS2Rs regulate host defense via genotype-specific pathways, as seen with TAS2R10 and TAS2R43. Polymorphisms in TAS2Rs affect infection susceptibility and immune responses, with implications for diseases like cystic fibrosis, chronic rhinosinusitis, dental caries, and periodontitis. Notably, TAS2R-mediated responses are highly tissue- and bacteria-dependent, with distinct signaling and outcomes observed depending on the pathogen and the local immune environment.

Conclusions: TAS2Rs play an essential role in host-pathogen interactions across multiple mucosal surfaces. Their ability to detect bacterial signals and activate innate immune defenses positions them as promising therapeutic targets. Future studies should focus on in vivo validation, genetic diversity, and receptor-ligand specificity using emerging tools like cryo-electron microscopy and transgenic models.

Keywords: GPCRs; TAS2Rs; bacterial infection; bitter taste receptors; innate immunity; mucosal immunity; quorum sensing; therapeutic targets.

Figure 1

TAS2R activation and underlying signaling mechanism. A bitter compound binds to the TAS2R, resulting in G_αgust activation via the exchange of GDP for GTP. G_αgust activates an intracellular phosphodiesterase which breaks down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), decreasing their intracellular levels. The βγ13 subunit of the G protein activates PLCβ2, which cleaves phosphatidylinositol 4,5‐bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol 1,4,5‐triphosphate (IP₃). IP₃ activates IP₃R3 located on the plasma membrane of the smooth endoplasmic reticulum, triggering Ca²⁺ release. Ca²⁺ binds and activates the TRPM5 (transient receptor potential cation channel subfamily M member 5) ion channel, resulting in Na⁺ influx and membrane depolarization. The figure was created with Biorender.

Figure 2

TAS2R38 detects P. aeruginosa acyl‐homoserine lactones (AHLs) in the airway to trigger mucociliary clearance. P. aeruginosa AHLs bind to TAS2R38 in the upper respiratory tract, resulting in nitric oxide (NO) production. NO diffuses into the air‐liquid interface (ALI), where it has direct bactericidal effects against P. aeruginosa. TAS2R38 triggers increased ciliary beating frequency (CBF) and enhanced mucociliary clearance, mediated by protein kinase G. The figure was created with Biorender.

Figure 3

P. aeruginosa quorum sensing molecules (QSMs) activate TAS2Rs in tracheal brush cells to initiate an immune response. This activation results in the release of the neuropeptides substance P (SP) and calcitonin gene‐related peptide (CGRP) from sensory neurons, resulting in leukocyte recruitment from blood vessels to the site of infection. The figure was created with Biorender.

Figure 4

Thaumatin‐derived bitter peptides modulate gastric immunity via TAS2R16 activation. Upon gastric digestion, the sweet‐tasting protein thaumatin is broken down into bitter peptides (DAGGRQLNSGES, FNVPMDF, WTINVEPGTKGGKIW), which are detected at physiologically relevant concentrations. These peptides activate the bitter taste receptor TAS2R16 on gastric parietal HGT‐1 cells, triggering proton secretion and downregulating Helicobacter pylori‐induced IL‐17 production. The figure was created with Biorender.