Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Cell Rep Med. 2020 Nov 17;1(8):100142. doi: 10.1016/j.xcrm.2020.100142. Epub 2020 Oct 29.
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.
酸性鞘磷脂酶/神经酰胺系统在细菌和病毒感染中发挥着重要作用。在这里，我们报告称，使用阿米替林、丙咪嗪、氟西汀、舍曲林、依地普仑或马普替林进行酸性鞘磷脂酶的药理抑制，或通过遗传下调该酶，可以防止严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）或水疱性口炎病毒（VSV）假病毒颗粒（pp-VSV）感染培养细胞或新鲜分离的人鼻上皮细胞，这些 pp-VSV 呈现 SARS-CoV-2 刺突蛋白（pp-VSV-SARS-CoV-2 刺突），这是一种真正模拟 SARS-CoV-2 感染的系统。感染会激活酸性鞘磷脂酶，并在细胞表面引发神经酰胺的释放。中和或消耗表面神经酰胺可减少 pp-VSV-SARS-CoV-2 刺突的感染。用低剂量阿米替林治疗志愿者可防止新鲜分离的鼻上皮细胞感染 pp-VSV-SARS-CoV-2 刺突。这些数据证明了临床研究的合理性，即研究阿米替林（一种临床上使用近 60 年的安全药物）或其他功能上阻断酸性鞘磷脂酶的抗抑郁药是否可以预防 SARS-CoV-2 感染。
