COVID-19, mainly manifested as acute respiratory distress syndrome, has afflicted millions of people worldwide since 2019. Taste dysfunction is a common early-stage symptom of COVID-19 infection that burdens patients for weeks or even permanently in some cases. Owing to its subjectivity and complexity, the mechanism of taste disorder is poorly studied. Previous studies have reported that the COVID-19 entry receptors are highly expressed in taste buds, thereby intensifying the cytocidal effect. Taste receptor cells are vulnerable to inflammation, and the COVID-19–induced cytokine storm causes secondary damage to taste function. Interferon and various proinflammatory cytokines can trigger cell apoptosis and disrupt the renewal of taste bud stem cells. This immune response can be further enhanced by the accumulation of Angiotensin II (Ang II) caused by an unbalanced local renin-angiotensin system (RAS) system. In addition, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is neurotropic and can invade the brain through the olfactory bulb, affecting the nervous system. Other factors, such as host zinc deficiency, genetic susceptibility, sialic acid, and some neurotransmitters, also contribute to the pathogenesis process. Although several medical interventions have displayed effectiveness, only a few strategies exist for the treatment of postinfectious dysgeusia. Stem cell–based taste regeneration offers promise for long-term taste disorders. Clinical studies have demonstrated that stem cells can treat long COVID-19 through immune regulation. In dysgeusia, the differentiation of taste bud stem cells can be stimulated through exogenous epithelial-derived and neural-derived factors to regenerate taste buds. Tongue organoids are also emerging as functional taste buds, offering new insights into the study of taste regeneration. This review presents the current evidence of the pathogenesis of COVID-19–related dysgeusia, summarizes currently available treatments, and suggests future directions of taste regeneration therapy.
AbdelmaksoudAAGhweilAAHassanMHRashadAKhodearyAArefZFSayedMAAElsammanMKBazeedSES. 2021. Olfactory disturbances as presenting manifestation among Egyptian patients with COVID-19: possible role of zinc. Biol Trace Elem Res. 199(11):4101–4108.
2.
AdpaikarAAZhangSKimHYKimKWMoonSJLeeJMJungHS. 2022. Fine-tuning of epithelial taste bud organoid to promote functional recapitulation of taste reactivity. Cell Mol Life Sci. 79(4):211.
3.
BaigAMKhaleeqAAliUSyedaH. 2020. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 11(7):995–998.
4.
BarhamHPTahaMABroylesSTStevensonMMZitoBAHallCA. 2021. Association between bitter taste receptor phenotype and clinical outcomes among patients with COVID-19. JAMA Netw Open. 4(5):e2111410.
5.
Barreto-VieiraDFda SilvaMANGarciaCCMirandaMDMatosAdRCaetanoBCResendePCMottaFCSiqueiraMMGirard-DiasW, et al. 2021. Morphology and morphogenesis of SARS-CoV-2 in Vero-E6 cells. Mem Inst Oswaldo Cruz. 116:e200443.
6.
BhatiaSLausterDBarduaMLudwigKAngioletti-UbertiSPoppNHoffmannUPaulusFBudtMStadtmüllerM, et al. 2017. Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo. Biomaterials. 138:22–34.
7.
BiancardiVCBomfimGFReisWLAl-GassimiSNunesKP. 2017. The interplay between angiotensin II, TLR4 and hypertension. Pharmacol Res. 120:88–96.
8.
CazzollaAPLoveroRLo MuzioLTestaNFSchirinziAPalmieriGPozzesserePProcacciVDi ComiteMCiavarellaD, et al. 2020. Taste and smell disorders in COVID-19 patients: role of interleukin-6. ACS Chem Neurosci. 11(17):2774–2781.
9.
CazzollaAPLoveroRSpiritoFDi CosolaMSantacroceLLo MuzioECiavarellaDDioguardiMCrincoliVPepeM, et al. 2023. Evaluation of qualitative and quantitative taste alterations in COVID-19. Biomol Biomed. 23(2):344–350.
10.
ChouHCChienCLHuangHLLuKS. 2001. Effects of zinc deficiency on the vallate papillae and taste buds in rats. J Formos Med Assoc. 100(5):326–335.
11.
ChoudhuryAMukherjeeS. 2020. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol. 92(10):2105–2113.
12.
CohnZJKimAHuangLBrandJWangH. 2010. Lipopolysaccharide-induced inflammation attenuates taste progenitor cell proliferation and shortens the life span of taste bud cells. BMC Neurosci. 11:72.
de SouzaVBFerreiraLTSene-FioreseMGarciaVRodriguesTZde Aquino JuniorAEBagnatoVSPanhocaVH. 2022. Photobiomodulation therapy for treatment olfactory and taste dysfunction COVID-19-related: a case report. J Biophotonics. 15(8):e202200058.
15.
DoyleMEAppletonALiuQRYaoQMazucantiCHEganJM. 2021. Human type II taste cells express angiotensin-converting enzyme 2 and are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Am J Pathol. 191(9):1511–1519.
16.
ElangovanS. 2022. Taste disorders and xerostomia are highly prevalent in patients with COVID-19. J Evid Based Dent Pract. 22(1):101687.
17.
GhodsKAlaeeA. 2022. Olfactory and taste disorders in patients suffering from covid-19, a review of literature. J Dent (Shiraz). 23(1):1–6.
18.
GonçalvesTJMGonçalvesSEABGuarnieriARisegatoRCGuimarãesMPde FreitasDCRazuk-FilhoAJuniorPBBParrilloEF. 2021. Association between low zinc levels and severity of acute respiratory distress syndrome by new coronavirus SARS-CoV-2. Nutr Clin Pract. 36(1):186–191.
19.
HeckmannSMHujoelPHabigerSFriessWWichmannMHeckmannJGHummelT. 2005. Zinc gluconate in the treatment of dysgeusia—a randomized clinical trial. J Dent Res. 84(1):35–38.
20.
HeidaRBhideYCGasbarriMKocabiyikOStellacciFHuckriedeALWHinrichsWLJFrijlinkHW. 2021. Advances in the development of entry inhibitors for sialic-acid-targeting viruses. Drug Discov Today. 26(1):122–137.
21.
HeninDPellegriniGCarmagnolaDLanza AttisanoGCLopezGFerreroSAmendolaADe AngelisDTanziEDellaviaC. 2022. Morphological and immunopathological aspects of lingual tissues in COVID-19. Cells. 11(7):1248.
22.
HenkinRIKnöppelABAbdelmeguidMStatemanWAHoseinS. 2017a. Sonic hedgehog is present in parotid saliva and is decreased in patients with taste dysfunction. J Oral Pathol Med. 46(9):829–833.
23.
HenkinRIKnöppelABAbdelmeguidMStatemanWAHoseinS. 2017b. Theophylline increases saliva sonic hedgehog and improves taste dysfunction. Arch Oral Biol. 82:263–270.
24.
HernessMSGilbertsonTA. 1999. Cellular mechanisms of taste transduction. Annu Rev Physiol. 61:873–900.
25.
HeveziPMoyerBDLuMGaoNWhiteEEcheverriFKalabatDSotoHLaitaBLiC, et al. 2009. Genome-wide analysis of gene expression in primate taste buds reveals links to diverse processes. PLoS One. 4(7):e6395.
26.
HoffmannMKleine-WeberHSchroederSKrügerNHerrlerTErichsenSSchiergensTSHerrlerGWuN-HNitscheA, et al. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 181(2):271–280.e8.
27.
HuBHuangSYinL. 2021. The cytokine storm and COVID-19. J Med Virol. 93(1):250–256.
28.
KlempinFMosienkoVMatthesSVillelaDCTodirasMPenningerJMBaderMSantosRASAleninaN. 2018. Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cell Mol Life Sci. 75(19):3625–3634.
29.
KocSCayliSAksakalCOcakliSSoyalicHSomukBTYüceS. 2016. Protective effects of melatonin and selenium against apoptosis of olfactory sensory neurons: a rat model study. Am J Rhinol Allergy. 30(3):62–66.
30.
KoyamaSKondoKUehaRKashiwadaniHHeinbockelT. 2021. Possible use of phytochemicals for recovery from COVID-19-induced anosmia and ageusia. Int J Mol Sci. 22(16):8912.
31.
LinXLuCOhmotoMChomaKMargolskeeRFMatsumotoIJiangP. 2021. R-spondin substitutes for neuronal input for taste cell regeneration in adult mice. Proc Natl Acad Sci U S A. 118(2):e2001833118.
32.
LiuLDDurickaDL. 2022. Stellate ganglion block reduces symptoms of long COVID: a case series. J Neuroimmunol. 362:577784.
33.
LyooKSKimHMLeeBCheYHKimSJSongDHwangWLeeSParkJHNaW, et al. 2022. Direct neuronal infection of SARS-CoV-2 reveals cellular and molecular pathology of chemosensory impairment of COVID-19 patients. Emerg Microbes Infect. 11(1):406–411.
34.
MilanettiEMiottoMDi RienzoLNagarajMMontiMGolbekTWGostiGRoetersSJWeidnerTOtzenDE, et al. 2021. In-silico evidence for a two receptor based strategy of SARS-CoV-2. Front Mol Biosci. 8:690655.
35.
NatafS. 2020. An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19. J Med Virol. 92(10):1743–1744.
36.
NetlandJMeyerholzDKMooreSCassellMPerlmanS. 2008. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 82(15):7264–7275.
37.
PushpassR-AGPellicciottaNKellyCProctorGCarpenterGH. 2019. Reduced salivary mucin binding and glycosylation in older adults influences taste in an in vitro cell model. Nutrients. 11(10):2280.
38.
RamasamySSubbianS. 2021. Critical determinants of cytokine storm and type I interferon response in COVID-19 pathogenesis. Clin Microbiol Rev. 34(3):e00299-20. Published erratum in Clin Microbiol Rev. 2021 Dec 15;34(4):e0016321.
39.
RissoDDraynaDMoriniG. 2020. Alteration, reduction and taste loss: main causes and potential implications on dietary habits. Nutrients. 12(11):3284.
40.
SakaguchiWKubotaNShimizuTSarutaJFuchidaSKawataAYamamotoYSugimotoMYakeishiMTsukinokiK. 2020. Existence of SARS-CoV-2 entry molecules in the oral cavity. Int J Mol Sci. 21(17):6000.
41.
SawaYIbaragiSOkuiTYamashitaJIkebeTHaradaH. 2021. Expression of SARS-CoV-2 entry factors in human oral tissue. J Anat. 238(6):1341–1354.
42.
ScottoGFazioVLo MuzioELo MuzioLSpiritoF. 2022. SARS-CoV-2 infection and taste alteration: an overview. Life (Basel). 12(5):690.
43.
ShechtmanLAPiarowskiCMScottJKGoldenEJGaillardDBarlowLA. 2021. Generation and culture of lingual organoids derived from adult mouse taste stem cells. J Vis Exp. (170):10.3791/62300.
44.
SheltonJFShastriAJFletez-BrantK, The 23andMe COVID-19 Team, AslibekyanSAutonA. 2022. The UGT2A1/UGT2A2 locus is associated with COVID-19-related loss of smell or taste. Nat Genet. 54(2):121–124.
45.
ShiT-HHuangY-LChenC-CPiW-CHsuY-LLoL-CChenW-YFuS-LLinC-H. 2020. Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage. Biochem Biophys Res Commun. 533(3):467–473.
46.
ShigemuraNTakaiSHiroseFYoshidaRSanematsuKNinomiyaY. 2019. Expression of renin-angiotensin system components in the taste organ of mice. Nutrients. 11(9):2251.
47.
ShirahashiRSudaTTamanoM. 2021. Hypozincemia in chronic hepatitis C is improved with viral clearance by direct-acting antiviral agents. Intern Med. 60(5):675–680.
48.
SinghCVJainSParveenS. 2021. The outcome of fluticasone nasal spray on anosmia and triamcinolone oral paste in dysgeusia in COVID-19 patients. Am J Otolaryngol. 42(3):102892.
49.
SkalnyAVRinkLAjsuvakovaOPAschnerMGritsenkoVAAlekseenkoSISvistunovAAPetrakisDSpandidosDAAasethJ, et al. 2020. Zinc and respiratory tract infections: perspectives for COVID-19 (review). Int J Mol Med. 46(1):17–26.
50.
SmallDMPrescottJ. 2005. Odor/taste integration and the perception of flavor. Exp Brain Res. 166(3-4):345–357.
51.
TanBKJHanRZhaoJJTanNKWQuahESHTanCJChanYHTeoNWYCharnTCSeeA, et al. 2022. Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves. BMJ. 378:e069503.
52.
TanJYSimXYJWeeLEChuaY-YCherngBPZNgIMConceicaoEPWongT-JYangYAungMK, et al. 2021. A comparative study on the clinical features of COVID-19 with non-SARS-CoV-2 respiratory viral infections. J Med Virol. 93(3):1548–1555.
53.
TsuchiyaH. 2022. Gustatory and saliva secretory dysfunctions in COVID-19 patients with zinc deficiency. Life (Basel). 12(3):353.
54.
WangHZhouMBrandJHuangL. 2007. Inflammation activates the interferon signaling pathways in taste bud cells. J Neurosci. 27(40):10703–10713.
55.
WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020; [accessed 2023 May 30]. https://covid19.who.int/
56.
WilsonCELasherRSYangRDzowoYKinnamonJCFingerTE. 2022. Taste bud connectome: implications for taste information processing. J Neurosci. 42(5):804–816.
57.
XiRZhengXTizzanoM. 2022. Role of taste receptors in innate immunity and oral health. J Dent Res. 101(7):759–768.
58.
XuHZhongLDengJPengJDanHZengXLiTChenQ. 2020. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 12(1):8.
59.
ZhuNWangWLiuZLiangCWangWYeFHuangBZhaoLWangHZhouW, et al. 2020. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun. 11(1):3910.
