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T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection
Robert J. Lee, … , Danielle R. Reed, Noam A. Cohen
Robert J. Lee, … , Danielle R. Reed, Noam A. Cohen
Published October 8, 2012
Citation Information: J Clin Invest. 2012;122(11):4145-4159. https://doi.org/10.1172/JCI64240.
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Research Article Article has an altmetric score of 218

T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

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Abstract

Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection.

Authors

Robert J. Lee, Guoxiang Xiong, Jennifer M. Kofonow, Bei Chen, Anna Lysenko, Peihua Jiang, Valsamma Abraham, Laurel Doghramji, Nithin D. Adappa, James N. Palmer, David W. Kennedy, Gary K. Beauchamp, Paschalis-Thomas Doulias, Harry Ischiropoulos, James L. Kreindler, Danielle R. Reed, Noam A. Cohen

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Figure 2

PTC and Pseudomonas AHLs induce T2R38-dependent Ca2+ responses in sinonasal ALIs and in a heterologous expression system.

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PTC and Pseudomonas AHLs induce T2R38-dependent Ca2+ responses in sinona...
(A) Ca2+ responses to PTC and ATP stimulation (mean ± SEM; 12 PAV/PAV, 16 PAV/AVI, and 8 AVI/AVI cultures, n = 4 patients each). Inset: PTC responses on a larger scale. (B) Peak Ca2+ responses from patients in A. Results from individual patients were pooled and averaged; each independent observation represents 1 patient. Fluo-4 fluorescence after 5 minutes of PTC: 1.30 ± 0.027 (PAV/PAV), 1.14 ± 0.035 (PAV/AVI), and 1.06 ± 0.02 (AVI/AVI). (C) Fluo-4 traces (means from 10 cultures) during stimulation with 200 μM C4HSL and ATP. (D) Peak Ca2+ responses from C, averaged as described in B. Fluo-4 fluorescence after 5 minutes of C4HSL: 1.29 ± 0.03 (PAV/PAV), 1.14 ± 0.04 (PAV/AVI), and 1.10 ± 0.04 (AVI/AVI). (E and F) Experiments were performed as in C and D using 100 μM C12HSL and 3 cultures from 3 patients/genotype. Fluo-4 fluorescence after 10 minutes of C12HSL stimulation: 1.52 ± 0.08 (PAV/PAV), 1.28 ± 0.04 (PAV/AVI), and 1.14 ± 0.01 (AVI/AVI). (G) Peak Fluo-4 fluorescence (ΔF/F) in hTAS2R38- and Gα16gustducin44-expressing HEK293 cells in response to PTC (114% ± 4% PAV; –4% ± 1% AVI), C4HSL (61% ± 2% PAV; 0.3% ± 0.4% AVI), and C12HSL (73% ± 5% PAV; 3% ± 2% AVI), denatonium (Denat; 1% ± 2% PAV; 3% ± 1% AVI), and salicin (Sal; 1.4% ± 0.3% PAV; 3% ± 1% AVI). *P < 0.05, **P < 0.01, ANOVA with Tukey-Kramer analysis.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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