Treatment Protocol for COVID-19 Based on T2R Phenotype

Mohamed A Taha, Christian A Hall, Colin J Shortess, Richard F Rathbone, Henry P Barham, Mohamed A Taha, Christian A Hall, Colin J Shortess, Richard F Rathbone, Henry P Barham

Abstract

COVID-19 has become a global pandemic of the highest priority. Multiple treatment protocols have been proposed worldwide with no definitive answer for acure. A prior retrospective study showed association between bitter taste receptor 38 (T2R38) phenotypes and the severity of COVID-19. Based on this, we proposed assessing the different T2R38 phenotypes response towards a targeted treatment protocol. Starting July 2020 till December 2020, we tested subjects for T2R38 phenotypic expression (supertasters, tasters, and nontasters). Subjects who were subsequently infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (diagnosed via PCR) were included. Based on their taster status, supertasters were given dexamethasone for 4 days; tasters were given azithromycin and dexamethasone +/- hydroxychloroquine for 7 days; and nontasters were given azithromycin and dexamethasone for 12 days. Subjects were followed prospectively and their outcomes were documented. Seven hundred forty-seven COVID-19 patients were included, with 184 (24.7%) supertasters, 371 (49.6%) tasters, and192 (25.7%) nontasters. The average duration of symptoms with the treatment protocol was 5 days for supertasters, 8.1 days for tasters, and 16.2 days for nontasters. Only three subjects (0.4%) required hospitalization (3/3 nontasters). Targeted treatment protocol showed significant correlation (p < 0.05) based on patients' T2R38 phenotypic expression. Assessing treatment protocols for COVID-19 patients according to their T2R38 phenotype could provide insight into the inconsistent results obtained from the different studies worldwide. Further study is warranted on the categorization of patients based on their T2R38 phenotype.

Keywords: COVID-19; T2R38; bitter taste receptors; solitary chemosensory cells.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Most common symptoms in each group. Cough was a common variant for all groups.

References

    1. Barham H.P., Taha M.A., Hall C.A. Does phenotypic expression of bitter taste receptor T2R38 show association with COVID-19 severity? Int. Forum Allergy Rhinol. 2020;10:1255–1257. doi: 10.1002/alr.22692.
    1. Bassetti M., Vena A., Giacobbe D.R. The novel Chinese coronavirus (2019-nCoV) infections: Challenges for fighting the storm. Eur. J. Clin. Investig. 2020;50:e13209. doi: 10.1111/eci.13209.
    1. Parry J. Wuhan: Britons to be evacuated as scientists estimate 44 000 cases of 2019-nCOV in the city. BMJ. 2020;368:m351. doi: 10.1136/bmj.m351.
    1. Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV) Biosci. Trends. 2020;14:69–71. doi: 10.5582/bst.2020.01020.
    1. Zumla A., Hui D.S., Azhar E.I., Memish Z.A., Maeurer M. Reducing mortality from 2019-nCoV: Host-directed therapies should be an option. Lancet. 2020;395:e35–e36. doi: 10.1016/S0140-6736(20)30305-6.
    1. Zumla A., Chan J.F.W., Azhar E.I., Hui D.S.C., Yuen K.-Y. Coronaviruses—Drug discovery and therapeutic options. Nat. Rev. Drug Discov. 2016;15:327–347. doi: 10.1038/nrd.2015.37.
    1. Rao M., Dodoo E., Zumla A., Maeurer M. Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies. Front. Microbiol. 2019;10:962. doi: 10.3389/fmicb.2019.00962.
    1. Li D., Zhang J. Diet Shapes the Evolution of the Vertebrate Bitter Taste Receptor Gene Repertoire. Mol. Biol. Evol. 2014;31:303–309. doi: 10.1093/molbev/mst219.
    1. Avau B., Depoortere I. The bitter truth about bitter taste receptors: Beyond sensing bitter in the oral cavity. Acta Physiol. 2015;216:407–420. doi: 10.1111/apha.12621.
    1. Lu P., Zhang C.-H., Lifshitz L.M., Zhuge R. Extraoral bitter taste receptors in health and disease. J. Gen. Physiol. 2017;149:181–197. doi: 10.1085/jgp.201611637.
    1. Lee R.J., Cohen N.A. Taste receptors in innate immunity. Cell. Mol. Life Sci. 2015;72:217–236. doi: 10.1007/s00018-014-1736-7.
    1. Cohen N.A. The genetics of the bitter taste receptor T2R38 in upper airway innate immunity and implications for chronic rhinosinusitis. Laryngoscope. 2017;127:44–51. doi: 10.1002/lary.26198.
    1. Luo X.-C., Chen Z.-H., Xue J.-B., Zhao D.-X., Lu C., Li Y.-H., Li S.-M., Du Y.-W., Liu Q., Wang P., et al. Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells. Proc. Natl. Acad. Sci. USA. 2019;116:5564–5569. doi: 10.1073/pnas.1812901116.
    1. Behrens M., Meyerhof W. Bitter taste receptor research comes of age: From characterization to modulation of TAS2Rs. Semin. Cell Dev. Biol. 2013;24:215–221. doi: 10.1016/j.semcdb.2012.08.006.
    1. Kim U.K., Drayna D. Genetics of individual differences in bitter taste perception: Lessons from the PTC gene. Clin. Genet. 2004;67:275–280. doi: 10.1111/j.1399-0004.2004.00361.x.
    1. Lee R.J., Kofonow J.M., Rosen P.L., Siebert A.P., Chen B., Doghramji L., Xiong G., Adappa N.D., Palmer J.N., Kennedy D.W., et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Investig. 2014;124:1393–1405. doi: 10.1172/JCI72094.
    1. Åkerström S., Gunalan V., Keng C.T., Tan Y.-J., Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected. Virology. 2009;395:1–9. doi: 10.1016/j.virol.2009.09.007.
    1. Bufe B., Breslin P.A.S., Kuhn C., Reed D.R., Tharp C.D., Slack J.P., Kim U.-K., Drayna D., Meyerhof W. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr. Biol. 2005;15:322–327. doi: 10.1016/j.cub.2005.01.047.
    1. Meyerhof W., Batram C., Kuhn C., Brockhoff A., Chudoba E., Bufe B., Appendino G., Behrens M. The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors. Chem. Senses. 2010;35:157–170. doi: 10.1093/chemse/bjp092.
    1. Adappa N.D., Truesdale C.M., Ba A.D.W., Rn L.D., Mansfield C., Kennedy D.W., Palmer J.N., Cowart B.J., Cohen N.A. Correlation of T2R38 taste phenotype and in vitro biofilm formation from nonpolypoid chronic rhinosinusitis patients. Int. Forum Allergy Rhinol. 2016;6:783–791. doi: 10.1002/alr.21803.
    1. Rom D., Christensen J., Alvarado R., Sacks R., Harvey R. The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis. Rhinol. J. 2017;55:90–94. doi: 10.4193/Rhin16.181.
    1. Farquhar D.R., Kovatch K.J., Palmer J.N., Shofer F.S., Adappa N.D., Cohen N.A. Phenylthiocarbamide taste sensitivity is associated with sinonasal symptoms in healthy adults. Int. Forum Allergy Rhinol. 2014;5:111–118. doi: 10.1002/alr.21437.
    1. Workman A.D., Brooks S.G., Kohanski M.A., Blasetti M.T., Cowart B.J., Mansfield C., Kennedy D.W., Palmer J.N., Adappa N.D., Reed D.R., et al. Bitter and sweet taste tests are reflective of disease status in chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 2018;6:1078–1080. doi: 10.1016/j.jaip.2017.09.014.
    1. Douglas J.E., Cohen N.A. Taste Receptors Mediate Sinonasal Immunity and Respiratory Disease. Int. J. Mol. Sci. 2017;18:437. doi: 10.3390/ijms18020437.
    1. Kohanski M.A., Brown L., Orr M., Tan L.H., Adappa N.D., Palmer J.N., Rubenstein R.C., Cohen N.A. Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling. Respir. Res. 2021;22:31. doi: 10.1186/s12931-021-01631-0.
    1. Clark A.A., Liggett S.B., Munger S.D. Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J. 2012;26:4827–4831. doi: 10.1096/fj.12-215087.
    1. Levit A., Nowak S., Peters M., Wiener A., Meyerhof W., Behrens M., Niv M.Y. The bitter pill: Clinical drugs that activate the human bitter taste receptor TAS2R14. FASEB J. 2013;28:1181–1197. doi: 10.1096/fj.13-242594.
    1. Dotson C.D., Zhang L., Xu H., Shin Y.-K., Vigues S., Ott S.H., Elson A.E.T., Choi H.J., Shaw H., Egan J.M., et al. Bitter Taste Receptors Influence Glucose Homeostasis. PLoS ONE. 2008;3:e3974. doi: 10.1371/journal.pone.0003974.
    1. Jaggupilli A., Singh N., De Jesus V.C., Gounni M.S., Dhanaraj P., Chelikani P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics. FASEB J. 2018;33:501–517. doi: 10.1096/fj.201800521RR.
    1. Manson M.L., Säfholm J., Al-Ameri M., Bergman P., Orre A.-C., Swärd K., James A., Dahlén S.-E., Adner M. Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle. Eur. J. Pharmacol. 2014;740:302–311. doi: 10.1016/j.ejphar.2014.07.005.
    1. Pulkkinen V., Manson M.L., Säfholm J., Adner M., Dahlén S.-E. The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea. Am. J. Physiol. Cell. Mol. Physiol. 2012;303:L956–L966. doi: 10.1152/ajplung.00205.2012.
    1. Sharma P., Yi R., Nayak A.P., Wang N., Tang F., Knight M.J., Pan S., Oliver B., Deshpande D.A. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice. Sci. Rep. 2017;7:srep46166. doi: 10.1038/srep46166.
    1. Sharma P., Panebra A., Pera T., Tiegs B.C., Hershfeld A., Kenyon L.C., Deshpande D.A. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells. Am. J. Physiol. Cell. Mol. Physiol. 2016;310:L365–L376. doi: 10.1152/ajplung.00373.2015.
    1. McAlinden K.D., Deshpande D.A., Ghavami S., Xenaki D., Sohal S.S., Oliver B.G., Haghi M., Sharma P. Autophagy Activation in Asthma Airways Remodeling. Am. J. Respir. Cell Mol. Biol. 2019;60:541–553. doi: 10.1165/rcmb.2018-0169OC.
    1. Brockhoff A., Behrens M., Massarotti A., Appendino G.B., 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;55:6236–6243. doi: 10.1021/jf070503p.
    1. Hansen J.L., Reed D.R., Wright M.J., Martin N.G., Breslin P.A.S. Heritability and Genetic Covariation of Sensitivity to PROP, SOA, Quinine HCl, and Caffeine. Chem. Senses. 2006;31:403–413. doi: 10.1093/chemse/bjj044.
    1. Lee R.J., Xiong G., Kofonow J.M., Chen B., Lysenko A., Jiang P., Abraham V., Doghramji L., Adappa N.D., Palmer J.N., et al. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J. Clin. Investig. 2012;122:4145–4159. doi: 10.1172/JCI64240.
    1. Parker D., Prince A. Innate Immunity in the Respiratory Epithelium. Am. J. Respir. Cell Mol. Biol. 2011;45:189–201. doi: 10.1165/rcmb.2011-0011RT.
    1. Zhang Y., Hoon M.A., Chandrashekar J., Mueller K.L., Cook B., Wu D., Zuker C.S., Ryba N.J.P. Coding of sweet, bitter, and umami tastes: Different receptor cells sharing similar signaling pathways. Cell. 2003;112:293e301. doi: 10.1016/S0092-8674(03)00071-0.
    1. Iwata S., Yoshida R., Ninomiya Y. Taste transductions in taste receptor cells: Basic tastes and moreover. Curr. Pharm. Des. 2014;20:2684–2692. doi: 10.2174/13816128113199990575.
    1. Sollai G., Melis M., Pani D., Cosseddu P., Usai I., Crnjar R., Bonfiglio A., Barbarossa I.T. 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.
    1. Salathe M. Regulation of Mammalian Ciliary Beating. Annu. Rev. Physiol. 2007;69:401–422. doi: 10.1146/annurev.physiol.69.040705.141253.
    1. Hariri B.M., McMahon D.B., Chen B., Freund J.R., Mansfield C.J., Doghramji L.J., Adappa N.D., Palmer J.N., Kennedy D.W., Reed D.R., et al. Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor. J. Biol. Chem. 2017;292:8484–8497. doi: 10.1074/jbc.M116.771949.
    1. Yan C.H., Hahn S., McMahon D., Bonislawski D., Kennedy D.W., Adappa N.D., Palmer J.N., Jiang P., Lee R.J., Cohen N.A. Nitric Oxide Production is Stimulated by Bitter Taste Receptors Ubiquitously Expressed in the Sinonasal Cavity. Am. J. Rhinol. Allergy. 2017;31:85–92. doi: 10.2500/ajra.2017.31.4424.
    1. Hume D.A., Underhill D.M., Sweet M.J., Ozinsky A.O., Liew F.Y., 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. doi: 10.1186/1471-2172-2-11.
    1. Culic O., Erakovic V., Parnham M.J. Anti-inflammatory effects of macrolide antibiotics. Eur. J. Pharmacol. 2001;429:209–229. doi: 10.1016/S0014-2999(01)01321-8.
    1. Good J.T., Rollins D.R., Martin R.J. Macrolides in the treatment of asthma. Curr. Opin. Pulm. Med. 2012;18:76–84. doi: 10.1097/MCP.0b013e32834daff8.
    1. Rollins D.R., Beuther D.A., Martin R.J. Update on Infection and Antibiotics in Asthma. Curr. Allergy Asthma Rep. 2010;10:67–73. doi: 10.1007/s11882-009-0086-2.
    1. Gao X., Ray R., Xiao Y., Ishida K., Ray P. Macrolide antibiotics improve chemotactic and phagocytic capacity as well as reduce inflammation in sulfur mustard-exposed monocytes. Pulm. Pharmacol. Ther. 2010;23:97–106. doi: 10.1016/j.pupt.2009.10.010.
    1. Sleigh M.A., Blake J.R., Liron N. The propulsion of mucus by cilia. Am. Rev. Respir. Dis. 1988;137:726e741. doi: 10.1164/ajrccm/137.3.726.
    1. Kato A., Schleimer R.P. Beyond inflammation: Airway epithelial cells are at the interface of innate and adaptive immunity. Curr. Opin. Immunol. 2007;19:711–720. doi: 10.1016/j.coi.2007.08.004.
    1. Patel N.N., Kohanski M.A., Maina I.W., Bs V.T., Bs A.D.W., Tong C.C., Kuan E.C., Bosso J.V., Adappa N.D., Palmer J.N., 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;8:900–906. doi: 10.1002/alr.22142.
    1. Kohanski M.A., Workman A.D., Patel N.N., Hung L.-Y., Shtraks J.P., Chen B., Blasetti M., Doghramji L., Kennedy D.W., Adappa N.D., 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;142:460–469.e7. doi: 10.1016/j.jaci.2018.03.019.
    1. Deshpande D.A., Wang W.C.H., McIlmoyle E.L., Robinett K.S., Schillinger R.M., An S.S., Sham J.S.K., Liggett S.B. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat. Med. 2010;16:1299–1304. doi: 10.1038/nm.2237.
    1. Shah A.S., Ben-Shahar Y., Moninger T.O., Kline J.N., Welsh M.J. Motile Cilia of Human Airway Epithelia Are Chemosensory. Science. 2009;325:1131–1134. doi: 10.1126/science.1173869.
    1. Grassin-Delyle S., Abrial C., Brollo M., Fayad-Kobeissi S., Naline E., Devillier P. Characterization of the expression and the role of bitter taste receptors in human lung parenchyma and macrophages. Am. J. Respir. Crit. Care Med. 2014;189:A5749.
    1. Upadhyaya J.D., Singh N., Sikarwar A.S., Chakraborty R., Pydi S.P., Bhullar R.P., Dakshinamurti S., Chelikani P. Dextromethorphan mediated bitter taste receptor activation in the pulmonary circuit causes vasoconstriction. PLoS ONE. 2014;9:e110373. doi: 10.1371/journal.pone.0110373.
    1. Kaufman A.C., Colquitt L., Ruckenstein M.J., Bigelow D.C., Eliades S.J., Xiong G., Lin C., Reed D.R., Cohen N.A. Bitter Taste Receptors and Chronic Otitis Media. Otolaryngol. Neck Surg. 2021;12 doi: 10.1177/0194599820984788.
    1. Florindo H.F., Kleiner R., Vaskovich-Koubi D., Acúrcio R.C., Carreira B., Yeini E., Tiram G., Liubomirski Y., Satchi-Fainaro R. Immune-mediated approaches against COVID-19. Nat. Nanotechnol. 2020;15:630–645. doi: 10.1038/s41565-020-0732-3.
    1. Savarino A., Boelaert J.R., Cassone A., Majori G., Cauda R. Effects of chloroquine on viral infections: An old drug against today’s diseases. Lancet Infect. Dis. 2003;3:722–727. doi: 10.1016/S1473-3099(03)00806-5.
    1. Vincent M.J., Bergeron E., Benjannet S., Erickson B.R., Rollin P.E., Ksiazek T.G., Seidah N.G., Nichol S.T. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J. 2005;2:69. doi: 10.1186/1743-422X-2-69.
    1. Mennella J.A., Pepino M.Y., Duke F.F., Reed D.R. Age modifies the genotype-phenotype relationship for the bitter receptor TAS2R38. BMC Genet. 2010;11:60–69. doi: 10.1186/1471-2156-11-60.
    1. Mennella J.A., Reed D.R., Roberts K.M., Mathew P.S., Mansfield C.J. Age-Related Differences in Bitter Taste and Efficacy of Bitter Blockers. PLoS ONE. 2014;9:e103107. doi: 10.1371/journal.pone.0103107.
    1. 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/15.1.39.
    1. Whissell-Buechy D., Wills C. Male and female correlations for taster (P.T.C.) phenotypes and rate of adolescent development. Ann. Hum. Biol. 1989;16:131–146. doi: 10.1080/03014468700006982.
    1. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDAapproved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir. Res. 2020;178:104787. doi: 10.1016/j.antiviral.2020.104787.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe