{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:11:16Z","timestamp":1790878276976,"version":"4.1.0"},"reference-count":118,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Olfactory perception is an important physiological function for human well-being and health. Loss of olfaction, or anosmia, caused by viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received considerable attention, especially in persistent cases that take a long time to recover. This review discusses the integration of different components of the olfactory epithelium to serve as a structural and functional unit and explores how they are affected during viral infections, leading to the development of olfactory dysfunction. The review mainly focused on the role of receptors mediating the disruption of olfactory signal transduction pathways such as angiotensin converting enzyme 2 (ACE2), transmembrane protease serine type 2 (TMPRSS2), neuropilin 1 (NRP1), basigin (CD147), olfactory, transient receptor potential vanilloid 1 (TRPV1), purinergic, and interferon gamma receptors. Furthermore, the compromised function of the epithelial sodium channel (ENaC) induced by SARS-CoV-2 infection and its contribution to olfactory dysfunction are also discussed. Collectively, this review provides fundamental information about the many types of receptors that may modulate olfaction and participate in olfactory dysfunction. It will help to understand the underlying pathophysiology of virus-induced anosmia, which may help in finding and designing effective therapies targeting molecules involved in viral invasion and olfaction. To the best of our knowledge, this is the only review that covered all the receptors potentially involved in, or mediating, the disruption of olfactory signal transduction pathways during COVID-19 infection. This wide and complex spectrum of receptors that mediates the pathophysiology of olfactory dysfunction reflects the many ways in which anosmia can be therapeutically managed.<\/jats:p>","DOI":"10.3390\/ijms25158527","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T18:21:40Z","timestamp":1722882100000},"page":"8527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects"],"prefix":"10.3390","volume":"25","author":[{"given":"Noor N.","family":"Al-Saigh","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Ibn Sina University for Medical Sciences, Amman 16197, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani A.","family":"Harb","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Arts and Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4532-276X","authenticated-orcid":false,"given":"Shtaywy","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, School of Science, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eabc5801","DOI":"10.1126\/sciadv.abc5801","article-title":"Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia","volume":"6","author":"Brann","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/lary.29286","article-title":"Prevalence of olfactory dysfunction in coronavirus disease 2019 (COVID-19): A meta-analysis of 27,492 patients","volume":"131","author":"Saniasiaya","year":"2021","journal-title":"Laryngoscope"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chen, S., and Wang, S. (2023). The immune mechanism of the nasal epithelium in COVID-19\u2013related olfactory dysfunction. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1045009"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"von Bartheld, C.S., and Wan, L. (2023). Prevalence of olfactory dysfunction with the omicron variant of SARS-CoV-2: A systematic review and meta-aAnalysis. Cells, 12.","DOI":"10.3390\/cells12030430"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s11154-016-9364-1","article-title":"New chemosensory component in the US national health and nutrition examination survey (NHANES): First-year results for measured olfactory dysfunction","volume":"17","author":"Hoffman","year":"2016","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1177\/1945892420946254","article-title":"The Prevalence of olfactory dysfunction in the general population: A systematic review and meta-analysis","volume":"35","author":"Desiato","year":"2021","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1177\/1073858417703910","article-title":"Olfactory loss and regain: Lessons for neuroplasticity","volume":"24","author":"Reichert","year":"2018","journal-title":"Neuroscientist"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/chemse\/bjz019","article-title":"Mammalian taste cells express functional olfactory receptors","volume":"44","author":"Malik","year":"2019","journal-title":"Chem. Senses"},{"key":"ref_9","first-page":"454","article-title":"Olfactory disorders: The patients\u2019 view","volume":"47","author":"Landis","year":"2009","journal-title":"Rhinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00408-021-00448-4","article-title":"Post-viral anosmia (loss of sensation of smell) did not begin with COVID-19!","volume":"199","author":"Dicpinigaitis","year":"2021","journal-title":"Lung"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.molmed.2022.06.005","article-title":"Olfactory dysfunction in COVID-19: Pathology and long-term implications for brain health","volume":"28","author":"Doty","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104176","DOI":"10.1016\/j.amjoto.2023.104176","article-title":"Comparison of the incidence of smell and taste disorders between influenza and COVID-19","volume":"45","author":"Cabrera","year":"2024","journal-title":"Am. J. Otolaryngol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103607","DOI":"10.1016\/j.amjoto.2022.103607","article-title":"Recovery from COVID-19 smell loss: Two-years of follow up","volume":"43","author":"McWilliams","year":"2022","journal-title":"Am. J. Otolaryngol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/joim.13209","article-title":"Prevalence and 6-month recovery of olfactory dysfunction: A multicentre study of 1363 COVID-19 patients","volume":"290","author":"Lechien","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e054598","DOI":"10.1136\/bmjopen-2021-054598","article-title":"Prevalence of olfactory dysfunction and quality of life in hospitalised patients 1 year after SARS-CoV-2 infection: A cohort study","volume":"12","author":"Tan","year":"2022","journal-title":"BMJ Open"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, X., Chiu, S.H., Tan, C.Y., and Chua, A.J. (2024). Long-term recovery from COVID-19 olfactory and gustatory dysfunction: A longitudinal study. Singap. Med. J., 10-4103.","DOI":"10.4103\/singaporemedj.SMJ-2022-174"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4921","DOI":"10.1007\/s10072-021-05611-6","article-title":"Qualitative smell\/taste disorders as sequelae of acute COVID-19","volume":"42","author":"Ercoli","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"o922","DOI":"10.1136\/bmj.o922","article-title":"COVID-19: Symptomatic infection with omicron variant is milder and shorter than with delta, study reports","volume":"377","author":"Wise","year":"2022","journal-title":"BMJ Brit. Med. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e160277","DOI":"10.1172\/jci.insight.160277","article-title":"SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways","volume":"7","author":"Verma","year":"2022","journal-title":"JCI Insight"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.cell.2022.01.024","article-title":"Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia","volume":"185","author":"Zazhytska","year":"2022","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s13365-023-01117-3","article-title":"Coronavirus infection in chemosensory cells","volume":"29","author":"Donadoni","year":"2023","journal-title":"J. Neurovirol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eabf8396","DOI":"10.1126\/scitranslmed.abf8396","article-title":"COVID-19\u2013related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters","volume":"13","author":"Lazarini","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Di Stadio, A., Bernitsas, E., La Mantia, I., Brenner, M.J., Ralli, M., Vaira, L.A., Colizza, A., Cavaliere, C., Laudani, M., and Frohman, T.C. (2023). Targeting neuroinflammation to alleviate chronic olfactory dysfunction in long covid: A role for investigating disease-modifying therapy (dmt)?. Life, 13.","DOI":"10.3390\/life13010226"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.tins.2022.11.003","article-title":"Olfactory dysfunction in COVID-19: New insights into the underlying mechanisms","volume":"46","author":"Butowt","year":"2023","journal-title":"Trends Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41588-021-00986-w","article-title":"The UGT2A1\/UGT2A2 locus is associated with COVID-19-related loss of smell or taste","volume":"54","author":"Shelton","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1152\/physrev.00012.2023","article-title":"Mechanisms of SARS-CoV-2-associated anosmia","volume":"103","author":"Tsukahara","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1152\/physrev.00035.2023","article-title":"Timing and cause of olfactory deciliation in COVID-19","volume":"104","author":"Butowt","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.bbi.2020.06.032","article-title":"Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters","volume":"89","author":"Bryche","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1093\/bib\/bbaa168","article-title":"The cellular basis of loss of smell in 2019-nCoV-infected individuals","volume":"22","author":"Gupta","year":"2021","journal-title":"Brief Bioinform."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1073\/pnas.0609215104","article-title":"AG protein\/cAMP signal cascade is required for axonal convergence into olfactory glomeruli","volume":"104","author":"Chesler","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rotermund, N., Schulz, K., Hirnet, D., and Lohr, C. (2019). Purinergic signaling in the vertebrate olfactory system. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00112"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/chemse\/bjaa040","article-title":"Anosmia in COVID-19: Mechanisms and significance","volume":"45","author":"Han","year":"2020","journal-title":"Chem. Senses"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101839","DOI":"10.1016\/j.isci.2020.101839","article-title":"SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain","volume":"23","author":"Fodoulian","year":"2020","journal-title":"iScience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/glia.20792","article-title":"Calcium store-mediated signaling in sustentacular cells of the mouse olfactory epithelium","volume":"57","author":"Hegg","year":"2009","journal-title":"Glia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1002\/stem.126","article-title":"Purinergic signaling regulates cell proliferation of olfactory epithelium progenitors","volume":"27","author":"Schwartz","year":"2009","journal-title":"Stem Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1002\/ar.1092060111","article-title":"Morphological relations between the receptor neurons, sustentacular cells and schwann cells in the olfactory mucosa of the salamander","volume":"206","author":"Rafols","year":"1983","journal-title":"Anat. Rec."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-3-642-14426-4_11","article-title":"Endocannabinoid modulation in the olfactory epithelium","volume":"52","author":"Breunig","year":"2010","journal-title":"Results Probl. Cell Differ."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2202-12-86","article-title":"Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium","volume":"12","author":"Dooley","year":"2011","journal-title":"BMC Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/1096-9861(20001009)426:1<1::AID-CNE1>3.0.CO;2-Y","article-title":"Mature olfactory receptor neurons express connexin 43","volume":"426","author":"Zhang","year":"2000","journal-title":"J. Comp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1016\/S0960-9822(02)01261-7","article-title":"Electrical coupling between mammalian cones","volume":"12","author":"DeVries","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/chemse\/bjx025","article-title":"Anosmia\u2014A clinical review","volume":"42","author":"Boesveldt","year":"2017","journal-title":"Chem. Senses"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/jemt.1070230203","article-title":"Fine structural aspects of secretion and extrinsic innervation in the olfactory mucosa","volume":"23","author":"Getchell","year":"1992","journal-title":"Microsc. Res. Tech."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev.physiol.64.082701.102219","article-title":"G proteins and olfactory signal transduction","volume":"64","author":"Ronnett","year":"2002","journal-title":"Annu. Rev. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1016\/j.cell.2021.10.027","article-title":"Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb","volume":"184","author":"Khan","year":"2021","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1021\/acschemneuro.0c00210","article-title":"Expression of the SARS-CoV-2 entry proteins, ACE2 and TMPRSS2, in cells of the olfactory epithelium: Identification of cell types and trends with age","volume":"11","author":"Bilinska","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Dong, M., Zhang, J., Ma, X., Tan, J., Chen, L., Liu, S., Xin, Y., and Zhuang, L. (2020). ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomed. Pharmacother., 131.","DOI":"10.1016\/j.biopha.2020.110678"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14614","DOI":"10.1128\/JVI.79.23.14614-14621.2005","article-title":"ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia","volume":"79","author":"Jia","year":"2005","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1007\/s00228-020-02963-4","article-title":"Inhibition of SARS-CoV-2 entry through the ACE2\/TMPRSS2 pathway: A promising approach for uncovering early COVID-19 drug therapies","volume":"76","author":"Ragia","year":"2020","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00970-21","DOI":"10.1128\/mBio.00970-21","article-title":"The TMPRSS2 inhibitor nafamostat reduces SARS-CoV-2 pulmonary infection in mouse models of COVID-19","volume":"12","author":"Li","year":"2021","journal-title":"mBio"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"104621","DOI":"10.1016\/j.micpath.2020.104621","article-title":"ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease","volume":"150","author":"Singh","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/s41564-020-0688-y","article-title":"Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses","volume":"5","author":"Letko","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Chupp, G., Spichler-Moffarah, A., S\u00f8gaard, O.S., Esserman, D., Dziura, J., Danzig, L., Chaurasia, R., Patra, K.P., Salovey, A., and Nunez, A. (2022). A phase 2 randomized, double-blind, placebo-controlled trial of oral camostat mesylate for early treatment of COVID-19 outpatients showed shorter illness course and attenuation of loss of smell and taste. MedRxiv.","DOI":"10.1101\/2022.01.28.22270035"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mayi, B.S., Leibowitz, J.A., Woods, A.T., Ammon, K.A., Liu, A.E., and Raja, A. (2021). The role of neuropilin-1 in COVID-19. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009153"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"zqaa024","DOI":"10.1093\/function\/zqaa024","article-title":"A pathophysiological model for COVID-19: Critical importance of transepithelial sodium transport upon airway infection","volume":"1","author":"Gentzsch","year":"2020","journal-title":"Function"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature02145","article-title":"Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus","volume":"426","author":"Li","year":"2003","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41467-020-20501-9","article-title":"Antibody neutralization of SARS-CoV-2 through ACE2 receptor mimicry","volume":"12","author":"Ge","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.cell.2020.05.042","article-title":"SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract","volume":"182","author":"Hou","year":"2020","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41392-020-00426-x","article-title":"CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells","volume":"5","author":"Wang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1007\/s11010-021-04130-4","article-title":"Possible role of purinergic signaling in COVID-19","volume":"476","author":"Franciosi","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"120482","DOI":"10.1016\/j.lfs.2022.120482","article-title":"Possible role of pannexin 1 channels and purinergic receptors in the pathogenesis and mechanism of action of SARS-CoV-2 and therapeutic potential of targeting them in COVID-19","volume":"297","author":"Nadeali","year":"2022","journal-title":"Life Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system","volume":"370","author":"Ojha","year":"2020","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.bbi.2020.12.031","article-title":"Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier?","volume":"95","author":"Burks","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1016\/j.bpj.2021.05.026","article-title":"Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of spike protein S1 and S2","volume":"120","author":"Li","year":"2021","journal-title":"Biophys. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2147\/BTT.S307352","article-title":"Neuropilin 1: A Novel entry factor for SARS-CoV-2 infection and a potential therapeutic target","volume":"15","author":"Abebe","year":"2021","journal-title":"Biol. Targets Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"105701","DOI":"10.1016\/j.micpath.2022.105701","article-title":"Discovery of natural products to block SARS-CoV-2 S-protein interaction with neuropilin-1 receptor: A molecular dynamics simulation approach","volume":"170","author":"Alshawaf","year":"2022","journal-title":"Microb. Pathog."},{"key":"ref_67","first-page":"4221","article-title":"Neuropilin-1 as a new potential SARS-CoV-2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID-19","volume":"22","author":"Davies","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1007\/s00401-021-02314-2","article-title":"The olfactory nerve is not a likely route to brain infection in COVID-19: A critical review of data from humans and animal models","volume":"141","author":"Butowt","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41583-023-00769-8","article-title":"The neurobiology of SARS-CoV-2 infection","volume":"25","author":"Meinhardt","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s00401-023-02664-z","article-title":"New evidence suggests SARS-CoV-2 neuroinvasion along the nervus terminalis rather than the olfactory pathway","volume":"147","author":"Butowt","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"612","DOI":"10.5483\/BMBRep.2012.45.11.232","article-title":"Olfactory receptors in non-chemosensory tissues","volume":"45","author":"Kang","year":"2012","journal-title":"BMB Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/brv.12348","article-title":"Disruptive physiology: Olfaction and the microbiome\u2013gut\u2013brain axis","volume":"93","author":"Bienenstock","year":"2017","journal-title":"Biol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41421-021-00290-1","article-title":"SARS-CoV-2 infection in the mouse olfactory system","volume":"7","author":"Ye","year":"2021","journal-title":"Cell Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"eadd0484","DOI":"10.1126\/scitranslmed.add0484","article-title":"Persistent post-COVID-19 smell loss is associated with inflammatory infiltration and altered olfactory epithelial gene expression","volume":"14","author":"Finlay","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1099\/0022-1317-83-9-2109","article-title":"Olfactory receptor neurons prevent dissemination of neurovirulent influenza a virus into the brain by undergoing virus-induced apoptosis","volume":"83","author":"Mori","year":"2002","journal-title":"J. Gen. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Du, Q., Liao, Q., Chen, C., Yang, X., Xie, R., and Xu, J. (2019). The role of transient receptor potential vanilloid 1 in common diseases of the digestive tract and the cardiovascular and respiratory system. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01064"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"242","DOI":"10.4193\/Rhin08.155","article-title":"Expression of transient receptor potential vanilloid (TRPV) families 1, 2, 3 and 4 in the mouse olfactory epithelium","volume":"47","author":"Ahmed","year":"2009","journal-title":"Rhinology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1177\/03331024211036665","article-title":"Activation of the trigeminal system as a likely target of SARS-CoV-2 may contribute to anosmia in COVID-19","volume":"42","author":"Messlinger","year":"2022","journal-title":"Cephalalgia"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1021\/acschemneuro.0c00249","article-title":"Proinflammatory cytokines in the olfactory mucosa result in COVID-19 induced anosmia","volume":"11","author":"Torabi","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1471-4159.2005.03524.x","article-title":"Tumor necrosis factor-\u03b1 stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons","volume":"96","author":"Bowen","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Meng, J., Wang, J., Steinhoff, M., and Dolly, J.O. (2016). TNF\u03b1 induces co-trafficking of TRPV1\/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18\u20131\/syntaxin1\/SNAP-25 mediated fusion. Sci. Rep., 6.","DOI":"10.1038\/srep21226"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/ejn.12066","article-title":"Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction","volume":"37","author":"Daiber","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1152\/jn.01253.2004","article-title":"Cyclic AMP cascade mediates the inhibitory odor response of isolated toad olfactory receptor neurons","volume":"94","author":"Madrid","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1002\/glia.20714","article-title":"Nucleotide-induced Ca2+ signaling in sustentacular supporting cells of the olfactory epithelium","volume":"56","author":"Kurtanska","year":"2008","journal-title":"Glia"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.ijporl.2010.03.030","article-title":"Blocking P2X receptors can inhibit the injury-induced proliferation of olfactory epithelium progenitor cells in adult mouse","volume":"74","author":"Gao","year":"2010","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"108150","DOI":"10.1016\/j.intimp.2021.108150","article-title":"Targeting purinergic receptors to suppress the cytokine storm induced by SARS-CoV-2 infection in pulmonary tissue","volume":"100","author":"Basso","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"23672","DOI":"10.3390\/ijms151223672","article-title":"P2X and P2Y receptors\u2014Role in the pathophysiology of the nervous system","volume":"15","author":"Tarnowski","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.neuroscience.2009.06.040","article-title":"Activation of purinergic receptors induces proliferation and neuronal differentiation in Swiss Webster mouse olfactory epithelium","volume":"163","author":"Jia","year":"2009","journal-title":"Neuroscience"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.neuroscience.2010.12.039","article-title":"ATP differentially upregulates fibroblast growth factor 2 and transforming growth factor alpha in neonatal and adult mice: Effect on neuroproliferation","volume":"177","author":"Jia","year":"2011","journal-title":"Neuroscience"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"101965","DOI":"10.1016\/j.jchemneu.2021.101965","article-title":"COVID-19 and Parkinson\u2019s disease: Defects in neurogenesis as the potential cause of olfactory system impairments and anosmia","volume":"115","author":"Rethinavel","year":"2021","journal-title":"J. Chem. Neuroanat."},{"key":"ref_91","first-page":"339","article-title":"Coronavirus COV-19\/SARS-CoV-2 affects women less than men: Clinical response to viral infection","volume":"34","author":"Conti","year":"2020","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Rawish, E., and Langer, H.F. (2022). Platelets and the role of P2X receptors in nociception, pain, neuronal toxicity and thromboinflammation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126585"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"8291","DOI":"10.1523\/JNEUROSCI.23-23-08291.2003","article-title":"Activation of purinergic receptor subtypes modulates odor sensitivity","volume":"23","author":"Hegg","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2014.05.055","article-title":"Purinergic signaling negatively regulates activity of an olfactory receptor in an odorant-dependent manner","volume":"275","author":"Yu","year":"2014","journal-title":"Neuroscience"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"19042","DOI":"10.1074\/jbc.M610781200","article-title":"Specificity of olfactory receptor interactions with other G protein-coupled receptors","volume":"282","author":"Bush","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e28383","DOI":"10.1002\/jmv.28383","article-title":"SARS-CoV-2 infection activates CREB\/CBP in cellular cyclic AMP-dependent pathways","volume":"95","author":"Yang","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0896-6273(04)00075-3","article-title":"Odorant stimulation enhances survival of olfactory sensory neurons via MAPK and CREB","volume":"41","author":"Watt","year":"2004","journal-title":"Neuron"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Liang, F. (2020). Sustentacular cell enwrapment of olfactory receptor neuronal dendrites: An update. Genes, 11.","DOI":"10.3390\/genes11050493"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41385-020-00359-2","article-title":"The central role of the nasal microenvironment in the transmission, modulation, and clinical progression of SARS-CoV-2 infection","volume":"14","author":"Gallo","year":"2021","journal-title":"Mucosal Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Ding, H., Wang, G., Yu, Z., Sun, H., and Wang, L. (2022). Role of interferon-gamma (IFN-\u03b3) and IFN-\u03b3 receptor 1\/2 (IFN\u03b3R1\/2) in regulation of immunity, infection, and cancer development: IFN-\u03b3-dependent or independent pathway. Biomed. Pharmacother., 155.","DOI":"10.1016\/j.biopha.2022.113683"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/088282403322396208","article-title":"Invasion and persistence of the neuroadapted influenza virus A\/WSN\/33 in the mouse olfactory system","volume":"16","author":"Aronsson","year":"2003","journal-title":"Viral Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.otohns.2009.06.090","article-title":"Biofilms correlate with TH1 inflammation in the sinonasal tissue of patients with chronic rhinosinusitis","volume":"141","author":"Hekiert","year":"2009","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/alr.21226","article-title":"Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage","volume":"3","author":"Pozharskaya","year":"2013","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.stem.2019.08.011","article-title":"Chronic inflammation directs an olfactory stem cell functional switch from neuroregeneration to immune defense","volume":"25","author":"Chen","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cytogfr.2020.06.001","article-title":"SARS-CoV-2 infection: The role of cytokines in COVID-19 disease","volume":"54","author":"Ruiz","year":"2020","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.cell.2020.09.050","article-title":"A mouse-adapted SARS-CoV-2 induces acute lung injury and mortality in standard laboratory mice","volume":"183","author":"Leist","year":"2020","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1021\/acschemneuro.0c00447","article-title":"Taste and smell disorders in COVID-19 patients: Role of interleukin-6","volume":"11","author":"Cazzolla","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced host response to SARS-CoV-2 drives development of COVID-19","volume":"181","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JCM.00811-21","article-title":"Indeterminate QuantiFERON Gold Plus results reveal deficient interferon gamma responses in severely ill COVID-19 patients","volume":"59","author":"Ward","year":"2021","journal-title":"J. Clin. Microbiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e58603","DOI":"10.7554\/eLife.58603","article-title":"SARS-CoV-2 strategically mimics proteolytic activation of human ENaC","volume":"9","author":"Anand","year":"2020","journal-title":"eLife"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"L14","DOI":"10.1152\/ajplung.2000.279.1.L14","article-title":"Distribution of ion transport mRNAs throughout murine nose and lung","volume":"279","author":"Rochelle","year":"2000","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.stem.2018.04.016","article-title":"Epithelial sodium channel regulates adult neural stem cell proliferation in a flow-dependent manner","volume":"22","author":"Petrik","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Brown, E.F., Mitaera, T., and Fronius, M. (2022). COVID-19 and liquid homeostasis in the lung-a perspective through the epithelial sodium channel (ENaC) lens. Cells, 11.","DOI":"10.3390\/cells11111801"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1016\/j.bpj.2021.06.005","article-title":"Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins","volume":"120","author":"Grant","year":"2021","journal-title":"Biophys. J."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ozdener, M.H., Mahavadi, S., Mummalaneni, S., and Lyall, V. (2022). Relationship between ENaC regulators and SARS-CoV-2 virus receptor (ACE2) expression in cultured adult human fungiform (HBO) taste cells. Nutrients, 14.","DOI":"10.3390\/nu14132703"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1152\/jn.01299.2004","article-title":"Electrical coupling in sustentacular cells of the mouse olfactory epithelium","volume":"94","author":"Vogalis","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/35093026","article-title":"How the olfactory system makes sense of scents?","volume":"413","author":"Firestein","year":"2001","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Rebholz, H., Braun, R.J., Ladage, D., Knoll, W., Kleber, C., and Hassel, A.W. (2020). Loss of olfactory function-early indicator for covid-19, other viral infections and neurodegenerative disorders. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.569333"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8527\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:30:08Z","timestamp":1760110208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,5]]},"references-count":118,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25158527"],"URL":"https:\/\/doi.org\/10.3390\/ijms25158527","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,5]]}}}