Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells
Open accessAbstract
The acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Here, we report that either pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram, or maprotiline or genetic downregulation of the enzyme prevents infection of cultured cells or freshy isolated human nasal epithelial cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or vesicular stomatitis virus (VSV) pseudoviral particles (pp-VSV) presenting SARS-CoV-2 spike protein (pp-VSV-SARS-CoV-2 spike), a bona fide system mimicking SARS-CoV-2 infection. Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treating volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike. The data justify clinical studies investigating whether amitriptyline, a safe drug used clinically for almost 60 years, or other antidepressants that functionally block acid sphingomyelinase prevent SARS-CoV-2 infection.
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Inhibition of acid sphingomyelinase may prevent infection of epithelial cells by SARS-CoV-2.
“First, prior studies suggest that several antidepressants may inhibit acid sphingomyelinase activity [10], which may prevent the infection of epithelial cells with SARS-CoV-2 [11].”
From Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study (2021) · cites this paper as [11]
Functional inhibitors of acid sphingomyelinase activity, including several SSRI and non-SSRI antidepressants, may prevent infection of epithelial cells with SARS-CoV-2.
“Furthermore, a recent study [10] suggests that functional inhibitors of acid sphingomyelinase activity (FIASMA), including several SSRI and non-SSRI antidepressants, may prevent the infection of epithelial cells with SARS-CoV-2 [11].”
From Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study (2021) · cites this paper as [11]
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- [30]Hoertel N. Sanchez Rico M. Verney R. Beeker N. Jannot A.-S. Neuraz A. Salamanca E. Paris N. Daniel C. Gramfort A. Association between SSRI antidepressant use and reduced risk of intubation or death in hospitalized patients with coronavirus disease 2019: a multicenter retrospective observational study medRxiv 2020 10.1101/2020.07.09.20143339.t · DOI
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Hoertel, N., Sánchez-Rico, M., Vernet, R., Beeker, N., Jannot, A.-S., Neuraz, A., Salamanca, E., Paris, N., Daniel, C., Gramfort, A., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01021-4 · Cited by 269 · see citing works
- Authors
- Carpinteiro, A., Edwards, M. J., Hoffmann, M., Kochs, G., Gripp, B., Weigang, S., Adams, C., Carpinteiro, E., Gulbins, A., Keitsch, S., Sehl, C., Soddemann, M., Wilker, B., Kamler, M., Bertsch, T., Lang, K. S., Patel, S., Wilson, G. C., Walter, S., Hengel, H., Pöhlmann, S., Lang, P. A., Kornhuber, J., Becker, K. A., Ahmad, S. A., Fassbender, K., & Gulbins, E.
- Affiliations
- Essen University Hospital (DE)
- University of Cincinnati (US)
- German Primate Center (DE)
- University of Freiburg (DE)
- Sana Kliniken AG (DE)
- University Children's Hospital Tübingen (DE)
- University of Duisburg-Essen (DE)
- Paracelsus Medizinische Privatuniversität (DE)
- Universitätsklinikum des Saarlandes (DE)
- Heinrich Heine University Düsseldorf (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Gulbins, Erich
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 1
- Issue
- 8
- Pages
- 100142
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7598530
- OpenAlex
- W3095260125
- Cited by
- 184
- References
- 41
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 20 · 2023: 32 · 2022: 54 · 2021: 62
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by-nc-nd)
- Funders
- Bundesministerium für Bildung und Forschung (01KI1723D)
- Deutsche Forschungsgemeinschaft (GU-335-38/1, Gu-335-35/1)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- acid sphingomyelinase, SARS-CoV-2, ceramide, nasal epithelial cells, amitriptyline, antidepressants, viral infection prevention, spike protein, drug repurposing
- MeSH terms
- SARS-CoV-2, Amitriptyline, Animals, Antidepressive Agents, Ceramides, Chlorocebus aethiops, Epithelial Cells, Humans, Nasal Mucosa, Sphingomyelin Phosphodiesterase, Vero Cells, Vesicular stomatitis Indiana virus, Neutral Ceramidase, Spike Glycoprotein, Coronavirus
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