We have recently demonstrated that the bitter taste receptor T2R38 is expressed in the upper airway and is activated by acyl-homoserine lactones (AHLs): quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Furthermore, we found that T2R38 regulates human upper airway innate defenses through nitric oxide production, which stimulates mucociliary clearance and has direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene, correlating with taste sensitivity to the molecule PTC, are linked to significant differences in the ability of uppe respiratory cells to clear and kill bacteria in response to AHLs. Based on these results, our central hypothesis is that the bitter taste receptor T2R38 expressed in the upper respiratory epithelium constitutes a sentinel defense network for the detection and clearance of microbes and that genetic variation in T2R38 contributes to individual differences in airway defensive capabilities. To test this hypothesis, we will: (1) determine whether TAS2R38 genotype, PTC taste sensitivity, and allele-specific expression correlate with symptom severity, disease burden, and interventional outcomes of chronic rhinosinusitis (CRS), and whether TAS2R38 polymorphisims not activated by AHLs are overrepresented in a cohort of CRS patient, and (2) identify other micorbial products that activate the common genetic variants of TAS2R38. The goal of these aims is to determine the role the bitter taste receptor T2R38 plays in upper airway defense and how common polymorphisms of this receptor contribute to upper airway disease. Furthermore, we will determine whether bitter taste sensitivity can be used as an indicator for disease severity in patients with chronic rhinosinusitis, and whether pharmacologic manipulation of this pathway has therapeutic potential.

Public Health Relevance

All people inhale harmful bacteria through the nose. In some, this results in respiratory infections. We propose that the bitter taste receptor T2R38 expressed in the airway senses bitter chemicals secreted by bacteria. When stimulated, this receptor triggers an antimicrobial response and eradicates the offending microbes. Thus, genetic differences in bitter taste receptor functionality may contribute to differences in the predisposition to airway infections.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013588-05
Application #
9483274
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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