Abstract
Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air-liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones.
Highlights
Bitter taste receptors, discovered in many tissues outside the tongue, have recently become potential therapeutic targets
T2R38 is expressed in the motile cilia of cells of the upper airway, and it is activated in response to acyl-homoserine lactone (AHL) quorum-sensing molecules secreted by Gram-negative bacteria [12], including the common airway pathogen Pseudomonas aeruginosa
Using the open-access online BitterX program that predicts the “bitterness” of a molecule [64], Pseudomonas quinolone signal (PQS) and DHQ were predicted to activate several T2Rs (Table S1), including T2R4, -14, and -16, which are expressed in sinonasal [9, 12, 14, 31, 32] and bronchial [10] motile cilia
Summary
Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa. There are 25 T2R isoforms on the human tongue, and many isoforms are expressed in organs such as the brain, nose and sinuses, lung, and reproductive tract (6 –10) The functions of these so-called “extraoral” taste receptors and their physiological ligands in many tissues are largely unknown, they may be responsible for some off-target effects of many commonly used medications that taste bitter (e.g. aspirin) [11]. T2R38 is expressed in the motile cilia of cells of the upper airway (nose and sinuses), and it is activated in response to acyl-homoserine lactone (AHL) quorum-sensing molecules secreted by Gram-negative bacteria [12], including the common airway pathogen Pseudomonas aeruginosa. Patients homozygous for the AVI TAS2R38 polymorphism, which results in nonfunctional T2R38 protein [22], are more susceptible to Gram-negative bacterial infection [12], have higher levels of sinonasal bacteria [23, 24] and biofilms [25], are at higher risk for chronic rhinosinusitis (26 –29), and may have worse outcomes after endoscopic sinus surgery [30] compared with patients homozygous for the functional (PAV) allele of TAS2R38
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