Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19
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Abstract
The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata. The authors demonstrate the presence of SARS-CoV-2 in the nasopharynx and brain, suggesting that the virus is present in the CNS and may enter through the olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue.
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SARS-CoV-2 invades the brain through the olfactory route and the vagus nerve, which may cause early olfactory loss, gastrointestinal and respiratory dysfunctions in COVID-19 patients.
“The neuroinvasive nature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) allows it to invade the brain through both the olfactory route and the vagus nerve, which may be an important mechanism for causing clinical symptoms such as early olfactory loss, gastrointestinal and respiratory dysfunctions in COVID-19 patients.270,271”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [271]
Autopsy evidence from COVID-19 patients demonstrates that SARS-CoV-2 enters the central nervous system partly through the olfactory mucosal-nervous milieu, supported by high viral RNA levels in the olfactory mucosa and presence of SARS-CoV spike protein in olfactory neurons.
“Autopsy evidences from COVID-19 patients directly demonstrated that SARS-CoV-2 enters the CNS partly through the olfactory mucosal-nervous milieu. This is supported by high viral RNA levels in the olfactory mucosa, and the presence of SARS-CoV spike protein in olfactory neurons.271”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [271]
Some control samples without viral infection had high cycle counts between 37 and 40, which previous work without such controls interpreted as evidence of neuroinvasion.
“Some of the samples from the control individuals without viral infection have high cycle counts (between 37 and 40), which in previous work (without such controls) has been interpreted as evidence of neuroinvasion9,18.”
From Dysregulation of brain and choroid plexus cell types in severe COVID-19 (2021) · cites this paper as [18]
A recent study pointed to the neural-mucosa interface in olfactory mucosa as a potential port of CNS entry for SARS-CoV-2.
“A recent study pointed out to the neural–mucosa interface in olfactory mucosa as a potential port of CNS entry for SARS-CoV-2 [167].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [167]
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Hosseini, S., & Korte, M. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220771 · Cited by 17 · see citing works
- Authors
- Meinhardt, J., Radke, J., Dittmayer, C., Franz, J., Thomas, C., Mothes, R., Laue, M., Schneider, J., Brünink, S., Greuel, S., Lehmann, M., Hassan, O., Aschman, T., Schumann, E., Chua, R. L., Conrad, C., Eils, R., Stenzel, W., Windgassen, M., Rößler, L., Goebel, H.-H., Gelderblom, H. R., Martin, H., Nitsche, A., Schulz-Schaeffer, W. J., Hakroush, S., Winkler, M. S., Tampe, B., Scheibe, F., Körtvélyessy, P., Reinhold, D., Siegmund, B., Kühl, A. A., Elezkurtaj, S., Horst, D., Oesterhelweg, L., Tsokos, M., Ingold-Heppner, B., Stadelmann, C., Drosten, C., Corman, V. M., Radbruch, H., & Heppner, F. L.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- Universitätsmedizin Göttingen (DE)
- Robert Koch Institute (DE)
- Heidelberg University (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Heppner, Frank L.
- ORCID
- Meinhardt, Jenny
- Radke, Josefine
- Dittmayer, Carsten
- Franz, Jonas
- Thomas, Carolina
- Mothes, Ronja
- Laue, Michael
- Schneider, Julia
- Greuel, Selina
- Lehmann, Malte
- Aschman, Tom
- Schumann, Elisa
- Chua, Robert Lorenz
- Conrad, Christian
- Eils, Roland
- Stenzel, Werner
- Nitsche, Andreas
- Hakroush, Samy
- Winkler, Martin S.
- Tampe, Björn
- Scheibe, Franziska
- Reinhold, Dirk
- Siegmund, Britta
- Kühl, Anja A.
- Elezkurtaj, Sefer
- Horst, David
- Tsokos, Michael
- Stadelmann, Christine
- Drosten, Christian
- Corman, Victor Max
- Radbruch, Helena
- Heppner, Frank L.
- Venue
- Nature Neuroscience
- Published
- 2020-11-30
- Volume
- 24
- Issue
- 2
- Pages
- 168-175
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W3106791064
- Cited by
- 1,458
- References
- 51
- Citations by year
- 2026: 56 · 2025: 108 · 2024: 194 · 2023: 249 · 2022: 411 · 2021: 408 · 2020: 30
- FWCI
- 119.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Publication server of the Robert Koch Institute (Robert Kock Institute) (submittedVersion, other-oa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
- DZNE Pub (submittedVersion)
- Robert-Koch-Institut (RKI)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- SARS-CoV-2, COVID-19 pandemic, olfactory epithelium, neurotropism, medulla oblongata, nasopharynx, neurological symptoms, olfactory nerve
- MeSH terms
- COVID-19, SARS-CoV-2, Brain, Central Nervous System, Humans, Olfactory Mucosa, RNA, Viral, Smell, Virus Internalization
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