Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells

Carpinteiro, Alexander; Edwards, Michael J.; Hoffmann, Markus; Kochs, Georg; Gripp, Barbara; Weigang, Sebastian; Adams, Constantin; Carpinteiro, Elisa; Gulbins, Anne; Keitsch, Simone; Sehl, Carolin; Soddemann, Matthias; Wilker, Barbara; Kamler, Markus; Bertsch, Thomas; Lang, Karl S.; Patel, Sameer; Wilson, Gregory C.; Walter, Silke; Hengel, Hartmut; Pöhlmann, Stefan; Lang, Philipp; Kornhuber, Johannes; Becker, Katrin Anne; Ahmad, Syed A.; Fassbender, Klaus; Gulbins, Erich

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 SARS-CoV-2 or pseudoviral pp-VSV-SARS-CoV-2 particles expressing 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.