T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

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

doi:10.1172/jci64240

Cited by 500 publications

(1,104 citation statements)

References 92 publications

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“…In contrast, on other mucosal surfaces, such as the urethral lining, these qualities represent potentially harmful (aversive) content. Bacteria produce and secrete bitter receptor-activating substances (5,37,38). In biofilms, such substances from the Gram-negative bacterium Pseudomonas aeruginosa, one of the predominant causative microorganisms in catheter-associated urinary tract infection (39), can reach concentrations as high as 600 μM (40).…”

Section: Discussionmentioning

confidence: 99%

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

Deckmann

Filipski

Krasteva‐Christ

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

148

214

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Significance We report the presence of a previously unidentified cholinergic, polymodal chemosensory cell in the mammalian urethra, the potential portal of entry for bacteria and harmful substances into the urogenital system. These cells exhibit structural markers of respiratory chemosensory cells (“brush cells”). They use the classical taste transduction cascade to detect potential hazardous compounds (bitter, umami, uropathogenic bacteria) and release acetylcholine in response. They lie next to sensory nerve fibers that carry acetylcholine receptors, and placing a bitter compound in the urethra enhances activity of the bladder detrusor muscle. Thus, monitoring of urethral content is linked to bladder control via a previously unrecognized cell type.

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Section: Discussionmentioning

confidence: 99%

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

Deckmann

Filipski

Krasteva‐Christ

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

148

214

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“…Taste Compounds-All analyzed compounds have been described previously in the literature as bitter tasting (100 -105) or as representing small molecules responsible for cell-tocell communications that have been conjectured to activate bitter taste receptors outside of the oral cavity (55,106). Bitter chemicals were purchased mainly from Sigma-Aldrich, Fluka (Oberhaching, Germany), ABCR (Karlsruhe, Germany), ICN Biochemicals (Aurora, USA), BioChemica (Darmstadt, Germany), ChromaDex (LGC Standard, Wesel, Germany), CPS ChemieϩService GmbH (Aachen, Germany), Cfm Oskar Tropitzsch (Marktredwitz, Germany), Carl Roth (Karlsruhe, Germany), and HWI Analytik (Rülzheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Our experiments revealed that mouse Tas2r105, as well as human TAS2R1, TAS2R10, and TAS2R14, is sensitive to various N-acyl homoserine lactones. We failed, however, to monitor N-acyl homoserine lactone responses for TAS2R38 (55), which may be explained by the use of different experimental methodologies. The ability to detect quorum-sensing molecules contributes to environmental adaptions and influences the behavior of eukaryotic organisms (84,85).…”

Section: Substancementioning

confidence: 97%

“…Interestingly, also four structurally related N-acyl homoserine lactones exclusively activated Tas2r105. These compounds are crucially involved in bacterial quorum sensing and induce antibacterial responses of the host (55).…”

Section: All Tas2r Genes Are Expressed In the Posterior Papillae Of Thementioning

confidence: 99%

“…The ability to detect quorum-sensing molecules contributes to environmental adaptions and influences the behavior of eukaryotic organisms (84,85). Humans homozygous for the non-taster allele of TAS2R38 are reported to be more susceptible to upper respiratory tract infections by Gram-negative bacteria than individuals carrying the taster variant of this receptor (55). It would be interesting to know if this also applies to those strains of mice harboring the less sensitive variant of Tas2r105 (7).…”

Section: Substancementioning

confidence: 99%

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Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Lossow

Hübner

Roudnitzky

et al. 2016

Journal of Biological Chemistry

195

277

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One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineagespecific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra.The plethora of natural compounds that taste bitter for humans comprises numerous chemicals with pharmacological activities that can make them powerful toxins, such as the alkaloids strychnine and colchicine or the sesquiterpene lactone picrotoxinin (1). However, compounds believed to exert health-beneficial effects such as the antioxidative phytoestrogen genistein from soy (2), the analgesic drug acetaminophen (3), or various polyphenols also taste bitter (4). To avoid ingestion of bitter substances that would pose a threat to organisms, efficient recognition and rejection mechanisms have developed throughout the animal kingdom. In bony vertebrates (Euteleostomi), the avoidance of bitter compounds is centered on taste receptors that detect potentially harmful substances with high accuracy and adequate sensitivity (5). Vertebrate bitter taste receptors, called taste 2 receptors (TAS2R (human) or Tas2r (murine)), 2 are G protein-coupled receptors only remotely related to other classes of this large and enormously versatile receptor family (6 -10). During evolution the first Tas2r genes appeared in the genomes of bony fish (11). In higher vertebrates frequent independent expansions and pseudogenization events resulted in differently sized Tas2r gene repertoires (12). Cons...

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Association Between Bitter Taste Receptor Phenotype and Clinical Outcomes Among Patients With COVID-19

et al. 2021

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IMPORTANCE Bitter taste receptors (T2Rs) have been implicated in sinonasal innate immunity, and genetic variation conferred by allelic variants in T2R genes is associated with variation in upper respiratory tract pathogen susceptibility, symptoms, and outcomes. Bitter taste receptor phenotype appears to be associated with the clinical course and symptom duration of SARS-CoV-2 infection.OBJECTIVE To evaluate the association between T2R phenotype and patient clinical course after infection with SARS-CoV-2. DESIGN, SETTING, AND PARTICIPANTSA prospective cohort study was performed from July 1 through September 30, 2020, at a tertiary outpatient clinical practice and inpatient hospital in the United States among 1935 participants (patients and health care workers) with occupational exposure to SARS-CoV-2. EXPOSURE Exposure to SARS-CoV-2. MAIN OUTCOMES AND MEASURES Participants underwent T2R38 phenotype taste testing to determine whether they were supertasters (those who experienced greater intensity of bitter tastes), tasters, or nontasters (those who experienced low intensity of bitter tastes or no bitter tastes) and underwent evaluation for lack of infection with SARS-CoV-2 via polymerase chain reaction (PCR) testing and IgM and IgG testing. A group of participants was randomly selected for genotype analysis to correlate phenotype. Participants were followed up until confirmation of infection with SARS-CoV-2 via PCR testing. Phenotype of T2R38 was retested after infection with SARS-CoV-2. The results were compared with clinical course. RESULTS A total of 1935 individuals (1101 women [56.9%]; mean [SD] age, 45.5 [13.9] years) participated in the study. Results of phenotype taste testing showed that 508 (26.3%) were supertasters, 917 (47.4%) were tasters, and 510 (26.4%) were nontasters. A total of 266 participants (13.7%) had positive PCR test results for SARS-CoV-2. Of these, 55 (20.7%) required hospitalization.Symptom duration among patients with positive results ranged from 0 to 48 days. Nontasters were significantly more likely than tasters and supertasters to test positive for SARS-CoV-2 (odds ratio, 10.1 [95% CI, 5.8-17.8]; P < .001), to be hospitalized once infected (odds ratio, 3.9 [1.5-10.2]; P = .006), and to be symptomatic for a longer duration (mean [SE] duration, 23.7 [0.5] days vs 13.5 [0.4] days vs 5.0 [0.6] days; P < .001). A total of 47 of 55 patients (85.5%) with COVID-19 who required inpatient admission were nontasters. Conversely, 15 of 266 patients (5.6%) with positive PCR test results were supertasters.CONCLUSIONS AND RELEVANCE This cohort study suggests that T2R38 receptor allelic variants were associated with participants' innate immune response toward SARS-CoV-2. The T2R phenotype was associated with patients' clinical course after SARS-CoV-2 infection. Nontasters were more likely (continued) Key Points Question What is the association between the bitter taste receptor phenotype and outcomes after infection with SARS-CoV-2? Findings In this cohort study of 1935 adults, 266 tested positive for...

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T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

Cited by 500 publications

References 92 publications

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Association Between Bitter Taste Receptor Phenotype and Clinical Outcomes Among Patients With COVID-19

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