Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells

被引：147

作者：

Carpinteiro, Alexander ^{[1
,2
]}

Edwards, Michael J. ^{[3
]}

Hoffmann, Markus ^{[4
,5
]}

Kochs, Georg ^{[6
,7
]}

Gripp, Barbara ^{[8
]}

Weigang, Sebastian ^{[6
,7
]}

Adams, Constantin ^{[9
]}

Carpinteiro, Elisa ^{[1
]}

Gulbins, Anne ^{[1
]}

Keitsch, Simone ^{[1
]}

Sehl, Carolin ^{[1
]}

Soddemann, Matthias ^{[1
]}

Wilker, Barbara ^{[1
]}

Kamler, Markus ^{[10
]}

Bertsch, Thomas ^{[11
]}

Lang, Karl S. ^{[12
]}

Patel, Sameer ^{[3
]}

Wilson, Gregory C. ^{[3
]}

Walter, Silke ^{[13
]}

Hengel, Hartmut ^{[6
,7
]}

Poehlmann, Stefan ^{[4
,5
]}

Lang, Philipp A. ^{[14
]}

Kornhuber, Johannes ^{[15
]}

Becker, Katrin Anne ^{[1
]}

Ahmad, Syed A. ^{[3
]}

Fassbender, Klaus ^{[13
]}

Gulbins, Erich ^{[1
,3
]}

机构：

[1] Univ Duisburg Essen, Inst Mol Biol, Hufelandstr 55, D-45122 Essen, Germany

[2] Univ Duisburg Essen, Univ Hosp Essen, Dept Hematol, Hufelandstr 55, D-45122 Essen, Germany

[3] Univ Cincinnati, Dept Surg, Med Sch, 231 Albert Sabin Way,ML0558, Cincinnati, OH 45267 USA

[4] German Primate Ctr, Infect Biol Unit, Leibniz Inst Primate Res, Gottingen, Germany

[5] Univ Gottingen, Fac Biol & Psychol, D-37073 Gottingen, Germany

[6] Univ Freiburg, Inst Virol, Hermann Herder Str 11, D-79104 Freiburg, Germany

[7] Univ Freiburg, Fac Med, Hermann Herder Str 11, D-79104 Freiburg, Germany

[8] Sana Klinikum Remscheid GmbH, Zentrum Seel Gesundheit Kindes & Jugendalters, Burger Str 211, D-42859 Remscheid, Germany

[9] Univ Hosp Tuebingen, Dept Paediat, D-72076 Tubingen, Germany

[10] Univ Duisburg Essen, Univ Hosp Essen, Dept Thorac & Cardiovasc Surg, Hufelandstr 55, D-45122 Essen, Germany

[11] Paracelsus Med Univ, Inst Clin Chem, Lab Med & Transfus Med, Nurnberg, Germany

[12] Univ Duisburg Essen, Inst Immunol, Hufelandstr 55, D-45147 Essen, Germany

[13] Univ Hosp Saarland, Dept Neurol, Kirrberger Str, D-66421 Homburg, Germany

[14] Heinrich Heine Univ, Med Fac, Dept Mol Med 2, Univ Str 1, D-40225 Dusseldorf, Germany

[15] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Psychiat & Psychotherapy, Schwabachanlage 6, D-91054 Erlangen, Germany

来源：

CELL REPORTS MEDICINE | 2020年 / 1卷 / 08期

关键词：

CERAMIDE; AMITRIPTYLINE; PROTEIN; ALPHA; SPIKE;

D O I：

10.1016/j.xcrm.2020.100142

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The acid sphingomyelinase/ceramide systemplays an important role in bacterial and viral infections. Here, we report that eitherpharmacological inhibitionofacidsphingomyelinasewithamitriptyline, 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.

引用

页数：16

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