Association Between Bitter Taste Receptor Phenotype and Clinical Outcomes Among Patients With COVID-19 | Infectious Diseases | JAMA Network Open | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Barham  HP, Taha  MA, Hall  CA.  Does phenotypic expression of bitter taste receptor T2R38 show association with COVID-19 severity?   Int Forum Allergy Rhinol. 2020;10(11):1255-1257. doi:10.1002/alr.22692 PubMedGoogle ScholarCrossref
Carey  RM, Adappa  ND, Palmer  JN, Lee  RJ, Cohen  NA.  Taste receptors: regulators of sinonasal innate immunity.   Laryngoscope Investig Otolaryngol. 2016;1(4):88-95. doi:10.1002/lio2.26 PubMedGoogle ScholarCrossref
Lee  RJ, Kofonow  JM, Rosen  PL,  et al.  Bitter and sweet taste receptors regulate human upper respiratory innate immunity.   J Clin Invest. 2014;124(3):1393-1405. doi:10.1172/JCI72094 PubMedGoogle ScholarCrossref
Lee  RJ, Xiong  G, Kofonow  JM,  et al.  T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection.   J Clin Invest. 2012;122(11):4145-4159. doi:10.1172/JCI64240 PubMedGoogle ScholarCrossref
Workman  AD, Palmer  JN, Adappa  ND, Cohen  NA.  The role of bitter and sweet taste receptors in upper airway immunity.   Curr Allergy Asthma Rep. 2015;15(12):72. doi:10.1007/s11882-015-0571-8 PubMedGoogle ScholarCrossref
Kim  UK, Drayna  D.  Genetics of individual differences in bitter taste perception: lessons from the PTC gene.   Clin Genet. 2005;67(4):275-280. doi:10.1111/j.1399-0004.2004.00361.x PubMedGoogle ScholarCrossref
Åkerström  S, Gunalan  V, Keng  CT, Tan  YJ, Mirazimi  A.  Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected.   Virology. 2009;395(1):1-9. doi:10.1016/j.virol.2009.09.007 PubMedGoogle ScholarCrossref
Bufe  B, Breslin  PA, Kuhn  C,  et al.  The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.   Curr Biol. 2005;15(4):322-327. doi:10.1016/j.cub.2005.01.047 PubMedGoogle ScholarCrossref
Meyerhof  W, Batram  C, Kuhn  C,  et al.  The molecular receptive ranges of human TAS2R bitter taste receptors.   Chem Senses. 2010;35(2):157-170. doi:10.1093/chemse/bjp092 PubMedGoogle ScholarCrossref
Adappa  ND, Truesdale  CM, Workman  AD,  et al.  Correlation of T2R38 taste phenotype and in vitro biofilm formation from nonpolypoid chronic rhinosinusitis patients.   Int Forum Allergy Rhinol. 2016;6(8):783-791. doi:10.1002/alr.21803 PubMedGoogle ScholarCrossref
Rom  DI, Christensen  JM, Alvarado  R, Sacks  R, Harvey  RJ.  The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis.   Rhinology. 2017;55(1):90-94. doi:10.4193/Rhin16.181 PubMedGoogle ScholarCrossref
Farquhar  DR, Kovatch  KJ, Palmer  JN, Shofer  FS, Adappa  ND, Cohen  NA.  Phenylthiocarbamide taste sensitivity is associated with sinonasal symptoms in healthy adults.   Int Forum Allergy Rhinol. 2015;5(2):111-118. doi:10.1002/alr.21437 PubMedGoogle ScholarCrossref
Workman  AD, Brooks  SG, Kohanski  MA,  et al.  Bitter and sweet taste tests are reflective of disease status in chronic rhinosinusitis.   J Allergy Clin Immunol Pract. 2018;6(3):1078-1080. doi:10.1016/j.jaip.2017.09.014 PubMedGoogle ScholarCrossref
Li  YC, Bai  WZ, Hashikawa  T.  The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.   J Med Virol. 2020;92(6):552-555. doi:10.1002/jmv.25728 PubMedGoogle ScholarCrossref
Hoffmann  M, Kleine-Weber  H, Schroeder  S,  et al.  SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.   Cell. 2020;181(2):271-280. doi:10.1016/j.cell.2020.02.052 PubMedGoogle ScholarCrossref
Brockhoff  A, Behrens  M, Massarotti  A, Appendino  G, Meyerhof  W.  Broad tuning of the human bitter taste receptor hTAS2R46 to various sesquiterpene lactones, clerodane and labdane diterpenoids, strychnine, and denatonium.   J Agric Food Chem. 2007;55(15):6236-6243. doi:10.1021/jf070503pPubMedGoogle ScholarCrossref
Hansen  JL, Reed  DR, Wright  MJ, Martin  NG, Breslin  PA.  Heritability and genetic covariation of sensitivity to PROP, SOA, quinine HCl, and caffeine.   Chem Senses. 2006;31(5):403-413. doi:10.1093/chemse/bjj044 PubMedGoogle ScholarCrossref
Sleigh  MA, Blake  JR, Liron  N.  The propulsion of mucus by cilia.   Am Rev Respir Dis. 1988;137(3):726-741. doi:10.1164/ajrccm/137.3.726 PubMedGoogle ScholarCrossref
Parker  D, Prince  A.  Innate immunity in the respiratory epithelium.   Am J Respir Cell Mol Biol. 2011;45(2):189-201. doi:10.1165/rcmb.2011-0011RT PubMedGoogle ScholarCrossref
Kato  A, Schleimer  RP.  Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity.   Curr Opin Immunol. 2007;19(6):711-720. doi:10.1016/j.coi.2007.08.004 PubMedGoogle ScholarCrossref
Patel  NN, Kohanski  MA, Maina  IW,  et al.  Solitary chemosensory cells producing interleukin-25 and group-2 innate lymphoid cells are enriched in chronic rhinosinusitis with nasal polyps.   Int Forum Allergy Rhinol. 2018. doi:10.1002/alr.22142 PubMedGoogle Scholar
Kohanski  MA, Workman  AD, Patel  NN,  et al.  Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps.   J Allergy Clin Immunol. 2018;142(2):460-469.e7. doi:10.1016/j.jaci.2018.03.019 PubMedGoogle ScholarCrossref
Hume  DA, Underhill  DM, Sweet  MJ, Ozinsky  AO, Liew  FY, Aderem  A.  Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state.   BMC Immunol. 2001;2(11):11. doi:10.1186/1471-2172-2-11 PubMedGoogle ScholarCrossref
Mennella  JA, Spector  AC, Reed  DR, Coldwell  SE.  The bad taste of medicines: overview of basic research on bitter taste.   Clin Ther. 2013;35(8):1225-1246. doi:10.1016/j.clinthera.2013.06.007 PubMedGoogle ScholarCrossref
Yamamoto  K, Ishimaru  Y.  Oral and extra-oral taste perception.   Semin Cell Dev Biol. 2013;24(3):240-246. doi:10.1016/j.semcdb.2012.08.005 PubMedGoogle ScholarCrossref
Pérez  CA, Margolskee  RF, Kinnamon  SC, Ogura  T.  Making sense with TRP channels: store-operated calcium entry and the ion channel Trpm5 in taste receptor cells.   Cell Calcium. 2003;33(5-6):541-549. doi:10.1016/S0143-4160(03)00059-9 PubMedGoogle ScholarCrossref
Zhang  Y, Hoon  MA, Chandrashekar  J,  et al.  Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways.   Cell. 2003;112(3):293-301. doi:10.1016/S0092-8674(03)00071-0 PubMedGoogle ScholarCrossref
Iwata  S, Yoshida  R, Ninomiya  Y.  Taste transductions in taste receptor cells: basic tastes and moreover.   Curr Pharm Des. 2014;20(16):2684-2692. doi:10.2174/13816128113199990575 PubMedGoogle ScholarCrossref
Sollai  G, Melis  M, Pani  D,  et al.  First objective evaluation of taste sensitivity to 6-n-propylthiouracil (PROP), a paradigm gustatory stimulus in humans.   Sci Rep. 2017;7:40353. doi:10.1038/srep40353 PubMedGoogle ScholarCrossref
Salathe  M.  Regulation of mammalian ciliary beating.   Annu Rev Physiol. 2007;69:401-422. doi:10.1146/annurev.physiol.69.040705.141253 PubMedGoogle ScholarCrossref
Mosimann  BL, White  MV, Hohman  RJ, Goldrich  MS, Kaulbach  HC, Kaliner  MA.  Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide increase in nasal secretions after allergen challenge in atopic patients.   J Allergy Clin Immunol. 1993;92(1 Pt 1):95-104. doi:10.1016/0091-6749(93)90043-FPubMedGoogle ScholarCrossref
Barham  HP, Cooper  SE, Anderson  CB,  et al.  Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa.   Int Forum Allergy Rhinol. 2013;3(6):450-457. doi:10.1002/alr.21149 PubMedGoogle ScholarCrossref
Hariri  BM, McMahon  DB, Chen  B,  et al.  Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor.   J Biol Chem. 2017;292(20):8484-8497. doi:10.1074/jbc.M116.771949PubMedGoogle ScholarCrossref
Yan  CH, Hahn  S, McMahon  D,  et al.  Nitric oxide production is stimulated by bitter taste receptors ubiquitously expressed in the sinonasal cavity.   Am J Rhinol Allergy. 2017;31(2):85-92. doi:10.2500/ajra.2017.31.4424PubMedGoogle ScholarCrossref
Mennella  JA, Pepino  MY, Duke  FF, Reed  DR.  Age modifies the genotype-phenotype relationship for the bitter receptor TAS2R38.   BMC Genet. 2010;11:60. doi:10.1186/1471-2156-11-60 PubMedGoogle ScholarCrossref
Mennella  JA, Reed  DR, Roberts  KM, Mathew  PS, Mansfield  CJ.  Age-related differences in bitter taste and efficacy of bitter blockers.   PLoS One. 2014;9(7):e103107. doi:10.1371/journal.pone.0103107 PubMedGoogle Scholar
Whissell-Buechy  D.  Effects of age and sex on taste sensitivity to phenylthiocarbamide (PTC) in the Berkeley guidance sample.   Chem Senses. 1990;15:39–57. doi:10.1093/chemse/15.1.39Google ScholarCrossref
Whissell-Buechy  D, Wills  C.  Male and female correlations for taster (P.T.C.) phenotypes and rate of adolescent development.   Ann Hum Biol. 1989;16(2):131-146. doi:10.1080/03014468700006982 PubMedGoogle ScholarCrossref
Davies  NG, Klepac  P, Liu  Y, Prem  K, Jit  M, Eggo  RM; CMMID COVID-19 working group.  Age-dependent effects in the transmission and control of COVID-19 epidemics.   Nat Med. 2020;26(8):1205-1211. doi:10.1038/s41591-020-0962-9 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    Main Supertaster T2R Expression Benefit May be Suppression of Cytokine Production
    George Anstadt, MD FACPM FACOEM | URMC
    Thanks to Barham et al for this careful documentation of a powerful protection against both clinically apparent Covid-19 illness and the severity of infection if acquired by those with the bitter super-taster phenotype. The practicality of assessing individual vulnerability to SARS CoV-2 infection using a simple taste test makes these findings clinically relevant.

    The author's proposed mechanisms of benefit are valid, but possibly they have overlooked the most important benefit. Surprisingly, bitter taste receptors (T2Rs) are expressed by alveolar macrophages, protectors of the type II pneumocyte, the ACE2- expressing tissue that is the Achilles heel of
    Covid-19 disease. When SARS CoV-2 virions deplete the ACE2 of these cells, dysregulation of the renin-angiotensin system occurs, unleashing the cytokine storm that is the usual fatal pathway. Experiments with TS2R agonists suggested the inhibition of cytokine production, which would likely be very beneficial in the deep lung of Covid-19 (1). Interestingly, the bitter TS2R agonist chloroquine was active in this 2019 test system, and the drug has proven effective as a Covid-19 therapy.


    Views 25,499
    Citations 0
    Original Investigation
    Infectious Diseases
    May 25, 2021

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

    Author Affiliations
    • 1Rhinology and Skull Base Research Group, Baton Rouge General Medical Center, Baton Rouge, Louisiana
    • 2Sinus and Nasal Specialists of Louisiana, Baton Rouge
    • 3Department of Otorhinolaryngology, Cairo University, Cairo, Egypt
    • 4Pennington Biomedical Research Center, Baton Rouge, Louisiana
    JAMA Netw Open. 2021;4(5):e2111410. doi:10.1001/jamanetworkopen.2021.11410
    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 SARS-CoV-2, and those who experienced low intensity of bitter tastes or no bitter tastes (nontasters) were significantly more likely to test positive for SARS-CoV-2, to be hospitalized, and to be symptomatic for a longer duration. Conversely, those who experienced greater intensity of bitter tastes (supertasters) represented 5.6% of patients infected with SARS-CoV-2, suggesting enhanced innate immune protection.

    Meaning  This study suggests that bitter taste receptor allelic variants are associated with innate immune fitness toward SARS-CoV-2 and can be used to correlate with clinical course and prognosis of COVID-19.


    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 Participants  A 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 to be infected with SARS-CoV-2 than the other 2 groups, suggesting enhanced innate immune protection against SARS-CoV-2.