Does the bitter taste receptor T2R38, expressed on the apical surface of the sinonasal epithelium, serve a sentinel role in microbial quorum-sensing communications and regulate localized innate biocidal defenses against bacterial biofilms associated with chronic rhinosinusitis (CRS)?
Bottom line: When stimulated by AHLs, T2R38 elicits calcium-dependent NO production that increases ciliary beat frequency and mucus clearance. This NO diffuses into the airway and contributes to innate antimicrobial effects.
Background: Multiple investigations have demonstrated an association between sinonasal bacterial biofilms and recalcitrant CRS. The sinonasal cavity is at the front line of defense of the respiratory tract via mucociliary clearance through ciliary beating. When sinonasal ciliated epithelial cells were stimulated with known T2R38-specific agonists, they exhibited calcium-dependent activation of nitric oxide (NO) synthase (NOS).
Study design: Live-cell imaging of DAF-FM in human sinonasal air–liquid interface (ALI) cultures.
Setting: The Department of Otorhinolaryngology—Head and Neck Surgery, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania; the Philadelphia Veterans Affairs Medical Center; and the Monell Chemical Senses Center, Philadelphia.
Synopsis: ALI cultures at days 0, 3, 6, 9, and 12 were subjected to double immunofluorescence staining with type IV b-tubulin, a marker for motile cilia, and T2R38. Merger of the images confirmed localization of T2R38 to sinonasal cilia, demonstrating that T2R38 expression is directly linked to ciliogenesis as no T2R38 expression was evident prior to cilia formation. Further experiments were performed to investigate whether cilia are necessary for T2R38-mediated production of NO; T2R38-mediated NO production was not evident prior to cilia formation.
Researchers also found that upper airway epithelial cells from individuals with one or two nonfunctional T2R38 alleles (AVI) have significantly blunted NO and ciliary responses following exposure to gram-negative quorum-sensing molecules; these individuals are more likely to be infected with gram-negative bacteria than those with two functional receptor alleles.
Possible limitations include some heterozygotes in the original data that may have been skewed and were poor expressers, which would explain both their low production of NO and susceptibility to CRS.