{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T01:29:11Z","timestamp":1768872551353,"version":"3.49.0"},"reference-count":131,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T00:00:00Z","timestamp":1635984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Academic research fund, MOE, Singapore","award":["R181-000-182-114"],"award-info":[{"award-number":["R181-000-182-114"]}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["COVID19RF2-0002"],"award-info":[{"award-number":["COVID19RF2-0002"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). It is known as a respiratory virus, but SARS-CoV-2 appears equally, or even more, infectious for the olfactory epithelium (OE) than for the respiratory epithelium in the nasal cavity. In light of the small area of the OE relative to the respiratory epithelium, the high prevalence of olfactory dysfunctions (ODs) in COVID-19 has been bewildering and has attracted much attention. This review aims to first examine the cytological and molecular biological characteristics of the OE, especially the microvillous apical surfaces of sustentacular cells and the abundant SARS-CoV-2 receptor molecules thereof, that may underlie the high susceptibility of this neuroepithelium to SARS-CoV-2 infection and damages. The possibility of SARS-CoV-2 neurotropism, or the lack of it, is then analyzed with regard to the expression of the receptor (angiotensin-converting enzyme 2) or priming protease (transmembrane serine protease 2), and cellular targets of infection. Neuropathology of COVID-19 in the OE, olfactory bulb, and other related neural structures are also reviewed. Toward the end, we present our perspectives regarding possible mechanisms of SARS-CoV-2 neuropathogenesis and ODs, in the absence of substantial viral infection of neurons. Plausible causes for persistent ODs in some COVID-19 convalescents are also examined.<\/jats:p>","DOI":"10.3390\/v13112225","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T22:25:54Z","timestamp":1636064754000},"page":"2225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["COVID-19 Anosmia: High Prevalence, Plural Neuropathogenic Mechanisms, and Scarce Neurotropism of SARS-CoV-2?"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1162-6212","authenticated-orcid":false,"given":"Fengyi","family":"Liang","sequence":"first","affiliation":[{"name":"Healthy Longevity Translational Research Program, Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"De Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Infectious Diseases Translational Research Program, Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/S1474-4422(20)30221-0","article-title":"Neurological Associations of COVID-19","volume":"19","author":"Ellul","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1001\/jamaneurol.2020.1127","article-title":"Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China","volume":"77","author":"Mao","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMc2019373","article-title":"Neuropathological Features of Covid-19","volume":"383","author":"Solomon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41582-020-00453-w","article-title":"Neurological Infection with SARS-CoV-2\u2014The Story so Far","volume":"17","author":"Solomon","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"622466","DOI":"10.3389\/fphys.2020.622466","article-title":"COVID-19-Associated Neurological Manifestations: An Emerging Electroencephalographic Literature","volume":"11","author":"Vellieux","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1111\/jnc.15197","article-title":"Viral Infection and Smell Loss: The Case of COVID-19","volume":"157","author":"Glezer","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.neuron.2020.06.032","article-title":"COVID-19 and the Chemical Senses: Supporting Players Take Center Stage","volume":"107","author":"Cooper","year":"2020","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1021\/acschemneuro.0c00251","article-title":"SARS-CoV-2, More than a Respiratory Virus: Its Potential Role in Neuropathogenesis","volume":"11","author":"Singal","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1515\/revneuro-2020-0039","article-title":"Anosmia: A Missing Link in the Neuroimmunology of Coronavirus Disease 2019 (COVID-19)","volume":"31","author":"Yazdanpanah","year":"2020","journal-title":"Rev. Neurosci."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1001\/jamaoto.2020.1379","article-title":"Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19","volume":"146","author":"Borsetto","year":"2020","journal-title":"JAMA Otolaryngol. Neck Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"672","DOI":"10.7326\/M20-2428","article-title":"Loss of Smell and Taste in 2013 European Patients With Mild to Moderate COVID-19","volume":"173","author":"Lechien","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11882-020-00961-1","article-title":"The Loss of Smell and Taste in the COVID-19 Outbreak: A Tale of Many Countries","volume":"20","author":"Mullol","year":"2020","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1177\/0194599820934376","article-title":"Olfactory and Gustatory Dysfunction as an Early Identifier of COVID-19 in Adults and Children: An International Multicenter Study","volume":"163","author":"Qiu","year":"2020","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1177\/0194599820926464","article-title":"Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 With Public Health Significance","volume":"163","author":"Sedaghat","year":"2020","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/0194599820926473","article-title":"The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-Analysis","volume":"163","author":"Tong","year":"2020","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/hed.26204","article-title":"Objective Evaluation of Anosmia and Ageusia in COVID-19 Patients: Single-center Experience on 72 Cases","volume":"42","author":"Vaira","year":"2020","journal-title":"Head Neck"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1007\/s00405-020-05999-5","article-title":"The Role of Self-Reported Olfactory and Gustatory Dysfunction as a Screening Criterion for Suspected COVID-19","volume":"277","author":"Wee","year":"2020","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1001\/jama.2020.8391","article-title":"Olfactory Dysfunction in COVID-19: Diagnosis and Management","volume":"323","author":"Whitcroft","year":"2020","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hajare, P.S., Harugop, A.S., Goswami, L., Padmavathy, O., Aggarwal, U., and Reddy, Y.L. (2021). Prevalence of Olfactory and Gustatory Dysfunction in Coronavirus Disease (COVID-19): A Cross Sectional Study in Our Tertiary Care Hospital. Indian J. Otolaryngol. Head Neck Surg., Epub ahead of print.","DOI":"10.1007\/s12070-021-02702-w"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1021\/acschemneuro.1c00542","article-title":"The D614G Virus Mutation Enhances Anosmia in COVID-19 Patients: Evidence from a Systematic Review and Meta-Analysis of Studies from South Asia","volume":"12","author":"Hagen","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1017\/S0022215120002455","article-title":"Olfactory Epithelium Histopathological Findings in Long-Term Coronavirus Disease 2019 Related Anosmia","volume":"134","author":"Vaira","year":"2020","journal-title":"J. Laryngol. Otol."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"bjab006","DOI":"10.1093\/chemse\/bjab006","article-title":"Six-Month Psychophysical Evaluation of Olfactory Dysfunction in Patients with COVID-19","volume":"46","author":"Menegaldo","year":"2021","journal-title":"Chem. Senses"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Boscolo-Rizzo, P., Guida, F., Polesel, J., Marcuzzo, A.V., Antonucci, P., Capriotti, V., Sacchet, E., Cragnolini, F., D\u2019Alessandro, A., and Zanelli, E. (2021). Self-Reported Smell and Taste Recovery in Coronavirus Disease 2019 Patients: A One-Year Prospective Study. Eur. Arch. Otorhinolaryngol., Epub ahead of print.","DOI":"10.1101\/2021.03.18.21253862"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1146\/annurev.ne.19.030196.002505","article-title":"Information Coding in the Vertebrate Olfactory System","volume":"19","author":"Buck","year":"1996","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6128","DOI":"10.1002\/anie.200501120","article-title":"Unraveling the Sense of Smell (Nobel Lecture)","volume":"44","author":"Buck","year":"2005","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/ar.10047","article-title":"Neural Regeneration and the Peripheral Olfactory System","volume":"269","author":"Schwob","year":"2002","journal-title":"Anat. Rec."},{"key":"ref_29","unstructured":"Standring, S., and Gray, H. (2009). Gray\u2019s Anatomy: The Anatomical Basis of Clinical Practice, Churchill Livingstone Elsevier. [40th ed.]."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Doty, R. (2003). Morphology of the Mammalian Olfactory Epithelium: Form, Fine Structure, Function, and Pathology. Handbook of Olfaction and Gustation, CRC Press.","DOI":"10.1201\/9780203911457-7"},{"key":"ref_31","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_32","unstructured":"Mescher, A.L. (2016). The Respiratory System. Junqueira\u2019s Basic Histology, McGraw-Hill Education. [14th ed.]."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF01206454","article-title":"Neurogenesis and Neuron Regeneration in the Olfactory System of Mammals. I. Morphological Aspects of Differentiation and Structural Organization of the Olfactory Sensory Neurons","volume":"8","author":"Graziadei","year":"1979","journal-title":"J. Neurocytol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/13550280590922793","article-title":"Olfactory Transmission of Neurotropic Viruses","volume":"11","author":"Mori","year":"2005","journal-title":"J. Neurovirol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.expneurol.2006.07.001","article-title":"The Risk Is in the Air: Intranasal Administration of MPTP to Rats Reproducing Clinical Features of Parkinson\u2019s Disease","volume":"202","author":"Prediger","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/path.4461","article-title":"The Olfactory Nerve: A Shortcut for Influenza and Other Viral Diseases into the Central Nervous System","volume":"235","author":"Verdijk","year":"2015","journal-title":"J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.expneurol.2012.12.010","article-title":"Anterograde Trafficking of Neurotrophin-3 in the Adult Olfactory System in Vivo","volume":"241","author":"Liu","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10078","DOI":"10.1128\/JVI.77.18.10078-10087.2003","article-title":"Enhanced Mucosal Immunoglobulin A Response of Intranasal Adenoviral Vector Human Immunodeficiency Virus Vaccine and Localization in the Central Nervous System","volume":"77","author":"Lemiale","year":"2003","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Hanson, L.R., and Frey, W.H. (2008). Intranasal Delivery Bypasses the Blood-Brain Barrier to Target Therapeutic Agents to the Central Nervous System and Treat Neurodegenerative Disease. BMC Neurosci., 9.","DOI":"10.1186\/1471-2202-9-S3-S5"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neuroscience.2008.05.040","article-title":"Nasal Administration of Cholera Toxin B Subunit\u2013Nerve Growth Factor Improves the Space Learning and Memory Abilities in \u03b2-Amyloid Protein25-35-Induced Amnesic Mice","volume":"155","author":"Zhang","year":"2008","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1089\/hum.2017.187","article-title":"Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I","volume":"28","author":"Belur","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s13311-019-00822-4","article-title":"Intranasal Insulin: A Treatment Strategy for Addiction","volume":"17","author":"Kashyap","year":"2020","journal-title":"Neurotherapeutics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/alr.22549","article-title":"Reversible Obstruction of the Olfactory Cleft: Impact on Olfactory Perception and Nasal Patency","volume":"10","author":"Besser","year":"2020","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/chemse\/bjl057","article-title":"Inflammatory Obstruction of the Olfactory Clefts and Olfactory Loss in Humans: A New Syndrome?","volume":"32","author":"Trotier","year":"2007","journal-title":"Chem. Senses"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/s41591-020-0916-2","article-title":"Real-Time Tracking of Self-Reported Symptoms to Predict Potential COVID-19","volume":"26","author":"Menni","year":"2020","journal-title":"Nat. Med."},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"2001948","DOI":"10.1183\/13993003.01948-2020","article-title":"Elevated ACE-2 Expression in the Olfactory Neuroepithelium: Implications for Anosmia and Upper Respiratory SARS-CoV-2 Entry and Replication","volume":"56","author":"Chen","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1023\/A:1016463118748","article-title":"The Influence of Drugs on Nasal Ciliary Movement","volume":"4","author":"Hermens","year":"1987","journal-title":"Pharm. Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Yaghi, A., and Dolovich, M. (2016). Airway Epithelial Cell Cilia and Obstructive Lung Disease. Cells, 5.","DOI":"10.3390\/cells5040040"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1146\/annurev-cellbio-100814-125234","article-title":"Structure, Regulation, and Functional Diversity of Microvilli on the Apical Domain of Epithelial Cells","volume":"31","author":"Sauvanet","year":"2015","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cne.902970102","article-title":"Morphology of the Human Olfactory Epithelium","volume":"297","author":"Morrison","year":"1990","journal-title":"J. Comp. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/jemt.1070230105","article-title":"Morphology of Olfactory Epithelium in Humans and Other Vertebrates","volume":"23","author":"Morrison","year":"1992","journal-title":"Microsc. Res. Tech."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/chemse\/27.7.623","article-title":"Biopsies of Human Olfactory Epithelium","volume":"27","author":"Jafek","year":"2002","journal-title":"Chem. Senses"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/cne.902500302","article-title":"Different Neuron Populations in the Feline Lateral Cervical Nucleus: A Light and Electron Microscopic Study with the Retrograde Axonal Transport Technique","volume":"250","author":"Flink","year":"1986","journal-title":"J. Comp. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"15148","DOI":"10.1073\/pnas.222546999","article-title":"Transneuronal Tracing of Diverse CNS Circuits by Cre-Mediated Induction of Wheat Germ Agglutinin in Transgenic Mice","volume":"99","author":"Braz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.pbiomolbio.2015.02.004","article-title":"Diverse Binding Modes, Same Goal: The Receptor Recognition Mechanism of Botulinum Neurotoxin","volume":"117","author":"Lam","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0006-8993(84)90940-5","article-title":"An Anterograde Neuroanatomical Tracing Method That Shows the Detailed Morphology of Neurons, Their Axons and Terminals: Immunohistochemical Localization of an Axonally Transported Plant Lectin, Phaseolus Vulgaris Leucoagglutinin (PHA-L)","volume":"290","author":"Gerfen","year":"1984","journal-title":"Brain Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/978-81-322-1777-0_6","article-title":"Neuroinvasive and Neurotropic Human Respiratory Coronaviruses: Potential Neurovirulent Agents in Humans","volume":"Volume 807","author":"Adhikari","year":"2014","journal-title":"Infectious Diseases and Nanomedicine I"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrmicro2260","article-title":"The Cell Biology of Rabies Virus: Using Stealth to Reach the Brain","volume":"8","author":"Schnell","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"684762","DOI":"10.3389\/fncel.2021.684762","article-title":"Engagement of Neurotropic Viruses in Fast Axonal Transport: Mechanisms, Potential Role of Host Kinases and Implications for Neuronal Dysfunction","volume":"15","author":"Richards","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0006-8993(81)91151-3","article-title":"Conjugates of Horseradish Peroxidase (HRP) with Cholera Toxin and Wheat Germ Agglutinin Are Superior to Free HRP as Orthogradely Transported Markers","volume":"223","author":"Trojanowski","year":"1981","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5405","DOI":"10.1128\/jvi.70.8.5405-5413.1996","article-title":"Anterograde, Transneuronal Transport of Herpes Simplex Virus Type 1 Strain H129 in the Murine Visual System","volume":"70","author":"Sun","year":"1996","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/chemse\/27.3.215","article-title":"Adenovirus-Mediated WGA Gene Delivery for Transsynaptic Labeling of Mouse Olfactory Pathways","volume":"27","author":"Kinoshita","year":"2002","journal-title":"Chem. Senses"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/B978-0-12-387040-7.00010-X","article-title":"Rabies Virus as a Transneuronal Tracer of Neuronal Connections","volume":"Volume 79","author":"Ugolini","year":"2011","journal-title":"Advances in Virus Research"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"ref_68","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_69","doi-asserted-by":"crossref","first-page":"5453","DOI":"10.1038\/s41467-020-19145-6","article-title":"ACE2 Localizes to the Respiratory Cilia and Is Not Increased by ACE Inhibitors or ARBs","volume":"11","author":"Lee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13195-016-0217-7","article-title":"Angiotensin-Converting Enzyme 2 Is Reduced in Alzheimer\u2019s Disease in Association with Increasing Amyloid-\u03b2 and Tau Pathology","volume":"8","author":"Kehoe","year":"2016","journal-title":"Alzheimers Res. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12974-021-02210-2","article-title":"Expression of SARS-CoV-2-Related Receptors in Cells of the Neurovascular Unit: Implications for HIV-1 Infection","volume":"18","author":"Torices","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 Facilitates SARS-CoV-2 Cell Entry and Infectivity","volume":"370","author":"Ojha","year":"2020","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41593-020-00758-5","article-title":"Olfactory Transmucosal SARS-CoV-2 Invasion as a Port of Central Nervous System Entry in Individuals with COVID-19","volume":"24","author":"Meinhardt","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S0140-6736(20)31525-7","article-title":"Inflammatory Olfactory Neuropathy in Two Patients with COVID-19","volume":"396","author":"Kirschenbaum","year":"2020","journal-title":"Lancet"},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and Transmission of SARS-CoV-2 in Golden Hamsters","volume":"583","author":"Sia","year":"2020","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1073\/pnas.2009799117","article-title":"Syrian Hamsters as a Small Animal Model for SARS-CoV-2 Infection and Countermeasure Development","volume":"117","author":"Imai","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1021\/acschemneuro.0c00649","article-title":"Regeneration Profiles of Olfactory Epithelium after SARS-CoV-2 Infection in Golden Syrian Hamsters","volume":"12","author":"Urata","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41467-020-20439-y","article-title":"Dose-Dependent Response to Infection with SARS-CoV-2 in the Ferret Model and Evidence of Protective Immunity","volume":"12","author":"Ryan","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/s41591-021-01296-8","article-title":"SARS-CoV-2 Infection of the Oral Cavity and Saliva","volume":"27","author":"Huang","year":"2021","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1021\/acsptsci.0c00062","article-title":"SARS-CoV-2 Receptor ACE2 Is Enriched in a Subpopulation of Mouse Tongue Epithelial Cells in Nongustatory Papillae but Not in Taste Buds or Embryonic Oral Epithelium","volume":"3","author":"Wang","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S1474-4422(20)30308-2","article-title":"Neuropathology of Patients with COVID-19 in Germany: A Post-Mortem Case Series","volume":"19","author":"Matschke","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e885","DOI":"10.1097\/PR9.0000000000000885","article-title":"Neurobiology of SARS-CoV-2 Interactions with the Peripheral Nervous System: Implications for COVID-19 and Pain","volume":"6","author":"McFarland","year":"2021","journal-title":"PAIN Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1056\/NEJMc2008597","article-title":"Neurologic Features in Severe SARS-CoV-2 Infection","volume":"382","author":"Helms","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1056\/NEJMc2009191","article-title":"Guillain\u2013Barr\u00e9 Syndrome Associated with SARS-CoV-2","volume":"382","author":"Toscano","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.bbi.2020.04.017","article-title":"Encephalitis as a Clinical Manifestation of COVID-19","volume":"88","author":"Ye","year":"2020","journal-title":"Brain. Behav. Immun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e242","DOI":"10.1016\/S2666-5247(20)30147-6","article-title":"Cerebrospinal Fluid Findings in COVID-19 Indicate Autoimmunity","volume":"1","author":"Lucchese","year":"2020","journal-title":"Lancet Microbe"},{"key":"ref_89","first-page":"e294","article-title":"CSF Biomarkers in Patients with COVID-19 and Neurological Symptoms: A Case Series","volume":"96","author":"Kanberg","year":"2020","journal-title":"Neurology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"117316","DOI":"10.1016\/j.jns.2021.117316","article-title":"Cerebrospinal Fluid in COVID-19: A Systematic Review of the Literature","volume":"421","author":"Lewis","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1056\/NEJMc2011400","article-title":"Multiorgan and Renal Tropism of SARS-CoV-2","volume":"383","author":"Puelles","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1016\/S2666-5247(20)30144-0","article-title":"Viral Presence and Immunopathology in Patients with Lethal COVID-19: A Prospective Autopsy Cohort Study","volume":"1","author":"Schurink","year":"2020","journal-title":"Lancet Microbe"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1111\/bpa.12889","article-title":"Neuropathologic Features of Four Autopsied COVID-19 Patients","volume":"30","author":"Kantonen","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_94","first-page":"1703","article-title":"Anosmia in COVID-19 Associated with Injury to the Olfactory Bulbs Evident on MRI","volume":"41","author":"Leal","year":"2020","journal-title":"Am. J. Neuroradiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1212\/WNL.0000000000009850","article-title":"Bilateral Transient Olfactory Bulb Edema during COVID-19\u2013Related Anosmia","volume":"95","author":"Laurendon","year":"2020","journal-title":"Neurology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.acra.2020.10.006","article-title":"Olfactory Bulb MRI and Paranasal Sinus CT Findings in Persistent COVID-19 Anosmia","volume":"28","author":"Kandemirli","year":"2021","journal-title":"Acad. Radiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41586-020-2334-5","article-title":"Infection of Dogs with SARS-CoV-2","volume":"586","author":"Sit","year":"2020","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41586-020-2324-7","article-title":"Respiratory Disease in Rhesus Macaques Inoculated with SARS-CoV-2","volume":"585","author":"Munster","year":"2020","journal-title":"Nature"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1126\/science.abb7015","article-title":"Susceptibility of Ferrets, Cats, Dogs, and Other Domesticated Animals to SARS\u2013Coronavirus 2","volume":"368","author":"Shi","year":"2020","journal-title":"Science"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Kumari, P., Rothan, H.A., Natekar, J.P., Stone, S., Pathak, H., Strate, P.G., Arora, K., Brinton, M.A., and Kumar, M. (2021). Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-HACE2 Mice. Viruses, 13.","DOI":"10.1101\/2020.12.14.422714"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-020-2943-z","article-title":"COVID-19 Treatments and Pathogenesis Including Anosmia in K18-HACE2 Mice","volume":"589","author":"Zheng","year":"2021","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/s41586-020-2312-y","article-title":"The Pathogenicity of SARS-CoV-2 in HACE2 Transgenic Mice","volume":"583","author":"Bao","year":"2020","journal-title":"Nature"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1113\/jphysiol.1974.sp010711","article-title":"Secretion and Electrogenesis of the Supporting Cell in the Olfactory Epithelium","volume":"242","author":"Okano","year":"1974","journal-title":"J. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/00001756-199209000-00007","article-title":"Immunolocalization of Two Cytochrome P450 Isozymes in Rat Nasal Chemosensory Tissue","volume":"3","author":"Chen","year":"1992","journal-title":"NeuroReport"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/(SICI)1096-9861(19961223)376:4<509::AID-CNE1>3.0.CO;2-5","article-title":"Supporting Cells as Phagocytes in the Olfactory Epithelium after Bulbectomy","volume":"376","author":"Suzuki","year":"1996","journal-title":"J. Comp. Neurol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s004410050030","article-title":"Olfactory Epithelium Consisting of Supporting Cells and Horizontal Basal Cells in the Posterior Nasal Cavity of Mice","volume":"299","author":"Suzuki","year":"2000","journal-title":"Cell Tissue Res."},{"key":"ref_107","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_108","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.neuroscience.2009.03.051","article-title":"Juxtanodin in the Rat Olfactory Epithelium: Specific Expression in Sustentacular Cells and Preferential Subcellular Positioning at the Apical Junctional Belt","volume":"161","author":"Tang","year":"2009","journal-title":"Neuroscience"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Genovese, F., and Tizzano, M. (2018). Microvillous Cells in the Olfactory Epithelium Express Elements of the Solitary Chemosensory Cell Transduction Signaling Cascade. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202754"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"12428","DOI":"10.1073\/pnas.1900083116","article-title":"Olfactory Sensory Neurons Mediate Ultrarapid Antiviral Immune Responses in a TrkA-Dependent Manner","volume":"116","author":"Sepahi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Rodriguez, S., Cao, L., Rickenbacher, G.T., Benz, E.G., Magdamo, C., Gomez, L.R., Holbrook, E.H., Albers, A.D., Gallagher, R., and Westover, M.B. (2020). Innate Immune Signaling in the Olfactory Epithelium Reduces Odorant Receptor Levels: Modeling Transient Smell Loss in COVID-19 Patients. medRxiv.","DOI":"10.1101\/2020.06.14.20131128"},{"key":"ref_112","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_113","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1523\/JNEUROSCI.4507-09.2010","article-title":"A Genetic Model of Chronic Rhinosinusitis-Associated Olfactory Inflammation Reveals Reversible Functional Impairment and Dramatic Neuroepithelial Reorganization","volume":"30","author":"Lane","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bbi.2019.02.012","article-title":"IL-17c Is Involved in Olfactory Mucosa Responses to Poly(I:C) Mimicking Virus Presence","volume":"79","author":"Bryche","year":"2019","journal-title":"Brain. Behav. Immun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"27","DOI":"10.20517\/2347-8659.2015.28","article-title":"Neuronal Toll-like Receptors and Neuro-Immunity in Parkinson\u2019s Disease, Alzheimer\u2019s Disease and Stroke","volume":"3","author":"Rietdijk","year":"2016","journal-title":"Neuroimmunol. Neuroinflamm."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00441-014-1848-2","article-title":"Innate Immune Responses and Neuroepithelial Degeneration and Regeneration in the Mouse Olfactory Mucosa Induced by Intranasal Administration of Poly(I:C)","volume":"357","author":"Kanaya","year":"2014","journal-title":"Cell Tissue Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3389\/fnmol.2018.00050","article-title":"Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium","volume":"11","author":"Crisafulli","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3389\/fimmu.2016.00475","article-title":"Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa","volume":"7","author":"Imamura","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1086\/590671","article-title":"Effect of Pretreatment with Toll-like Receptor Agonists in a Mouse Model of Herpes Simplex Virus Type 1 Encephalitis","volume":"198","author":"Boivin","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1111\/j.1460-9568.2005.04082.x","article-title":"Changes in Reelin Expression in the Mouse Olfactory Bulb after Chemical Lesion to the Olfactory Epithelium","volume":"21","author":"Yamamoto","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.neuron.2016.10.061","article-title":"Axonal Degeneration Is Regulated by a Transcriptional Program That Coordinates Expression of Pro- and Anti-Degenerative Factors","volume":"92","author":"Romi","year":"2016","journal-title":"Neuron"},{"key":"ref_122","first-page":"S0039625721001387","article-title":"Trans-Synaptic Degeneration in the Visual Pathway: Neural Connectivity, Pathophysiology, and Clinical Implications in Neurodegenerative Disorders","volume":"66","author":"Sharma","year":"2021","journal-title":"Surv. Ophthalmol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.devcel.2021.03.011","article-title":"An Anterograde Pathway for Sensory Axon Degeneration Gated by a Cytoplasmic Action of the Transcriptional Regulator P53","volume":"56","author":"Simon","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"16157","DOI":"10.1073\/pnas.0908201106","article-title":"C-End Rule Peptides Mediate Neuropilin-1-Dependent Cell, Vascular, and Tissue Penetration","volume":"106","author":"Teesalu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.neuron.2015.02.003","article-title":"Toll Receptors Instruct Axon and Dendrite Targeting and Participate in Synaptic Partner Matching in a Drosophila Olfactory Circuit","volume":"85","author":"Ward","year":"2015","journal-title":"Neuron"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"11605","DOI":"10.1038\/s41598-017-10229-w","article-title":"Lipopolysaccharide-Initiated Persistent Rhinitis Causes Gliosis and Synaptic Loss in the Olfactory Bulb","volume":"7","author":"Shimada","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/BF01175561","article-title":"Neurogenesis and Neuron Regeneration in the Olfactory System of Mammals. II. Degeneration and Reconstitution of the Olfactory Sensory Neurons after Axotomy","volume":"8","author":"Graziadei","year":"1979","journal-title":"J. Neurocytol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0006-8993(99)02075-2","article-title":"Regeneration of Olfactory Receptor Neurons Following Chemical Lesion: Time Course and Enhancement with Growth Factor Administration","volume":"849","author":"Herzog","year":"1999","journal-title":"Brain Res."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Brann, J.H., and Firestein, S.J. (2014). A Lifetime of Neurogenesis in the Olfactory System. Front. Neurosci., 8.","DOI":"10.3389\/fnins.2014.00182"},{"key":"ref_130","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_131","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"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2225\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:25:54Z","timestamp":1760167554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,4]]},"references-count":131,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["v13112225"],"URL":"https:\/\/doi.org\/10.3390\/v13112225","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,4]]}}}