The acid sphingomyelinase/ceramide system in COVID-19.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
21
01
2021
accepted:
14
09
2021
revised:
10
08
2021
pubmed:
6
10
2021
medline:
5
4
2022
entrez:
5
10
2021
Statut:
ppublish
Résumé
Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.
Identifiants
pubmed: 34608263
doi: 10.1038/s41380-021-01309-5
pii: 10.1038/s41380-021-01309-5
pmc: PMC8488928
doi:
Substances chimiques
Ceramides
0
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
307-314Informations de copyright
© 2021. The Author(s).
Références
Hoertel N, Blachier M, Blanco C, Olfson M, Massetti M, Rico MS, et al. A stochastic agent-based model of the SARS-CoV-2 epidemic in France. Nat Med. 2020;26:1417–21.
pubmed: 32665655
doi: 10.1038/s41591-020-1001-6
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8:475–81.
pubmed: 32105632
pmcid: 7102538
doi: 10.1016/S2213-2600(20)30079-5
Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020;20:669–77.
pubmed: 32240634
pmcid: 7158570
doi: 10.1016/S1473-3099(20)30243-7
Verstergaard LS, Nielsen J, Richter L, Schmid D, Bustos N, Braeye T, et al. Excess all-cause mortality during the COVID-19 pandemic in Europe—preliminary pooled estimates from the EuroMOMO network, March to April 2020. Eurosurveillance. 2020;25:1–6.
Zhou Y, Yang Q, Chi J, Dong B, Lv W, Shen L, et al. Comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease 2019: a systematic review and meta-analysis. Int J Infect Dis. 2020;99:47–56.
pubmed: 32721533
pmcid: 7381888
doi: 10.1016/j.ijid.2020.07.029
Mojtabavi H, Saghazadeh A, Rezaei N. Interleukin-6 and severe COVID-19: a systematic review and meta-analysis. Eur Cytokine Netw. 2020;31:44–9.
pubmed: 32933891
pmcid: 7530350
doi: 10.1684/ecn.2020.0448
Mulchandani R, Lyngdoh T, Kakkar AK. Deciphering the COVID-19 cytokine storm: systematic review and meta-analysis. Eur J Clin Invest. 2020;51:e13429.
pubmed: 33058143
Dhar SK, K V, Damodar S, Gujar S, Das M. IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon. 2021;7:e06155.
pubmed: 33553782
pmcid: 7846230
doi: 10.1016/j.heliyon.2021.e06155
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.
pubmed: 32015507
pmcid: 7095418
doi: 10.1038/s41586-020-2012-7
Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181:894–904.
pubmed: 32275855
pmcid: 7144619
doi: 10.1016/j.cell.2020.03.045
Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581:215–20.
pubmed: 32225176
doi: 10.1038/s41586-020-2180-5
Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260–3.
pubmed: 32075877
pmcid: 7164637
doi: 10.1126/science.abb2507
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.
pubmed: 32142651
pmcid: 7102627
doi: 10.1016/j.cell.2020.02.052
Grassmé H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, et al. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem. 2001;276:20589–96.
pubmed: 11279185
doi: 10.1074/jbc.M101207200
Grassmé H, Jendrossek V, Riehle A, von Kürthy G, Berger J, Schwarz H, et al. Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med. 2003;9:322–30.
pubmed: 12563314
doi: 10.1038/nm823
Schissel SL, Jiang X, Tweedie-Hardman J, Jeong T, Camejo EH, Najib J, et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem. 1998;273:2738–46.
pubmed: 9446580
doi: 10.1074/jbc.273.5.2738
Ferranti CS, Cheng J, Thompson C, Zhang J, Rotolo JA, Buddaseth S, et al. Fusion of lysosomes to plasma membrane initiates radiation-induced apoptosis. J Cell Biol. 2020;219:e201903176.
pubmed: 32328634
pmcid: 7147101
doi: 10.1083/jcb.201903176
Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol. 2000;184:285–300.
pubmed: 10911359
doi: 10.1002/1097-4652(200009)184:3<285::AID-JCP2>3.0.CO;2-3
Nurminen TA, Holopainen JM, Zhao H, Kinnunen PKJ. Observation of topical catalysis by sphingomyelinase coupled to microspheres. J Am Chem Soc. 2002;124:12129–34.
pubmed: 12371852
doi: 10.1021/ja017807r
Grassmé H, Bock J, Kun J, Gulbins E. Clustering of CD40 ligand is required to form a functional contact with CD40. J Biol Chem. 2002;277:30289–99.
pubmed: 12011072
doi: 10.1074/jbc.M200494200
Grassmé H, Henry B, Ziobro R, Becker KA, Riethmüller J, Gardner A, et al. β1-Integrin accumulates in cystic fibrosis luminal airway epithelial membranes and decreases sphingosine, promoting bacterial infections. Cell Host Microbe. 2017;21:707–18.
pubmed: 28552668
pmcid: 5475347
doi: 10.1016/j.chom.2017.05.001
Cremesti A, Paris F, Grassmé H, Holler N, Tschopp J, Fuks Z, et al. Ceramide enables fas to cap and kill. J Biol Chem. 2001;276:23954–61.
pubmed: 11287428
doi: 10.1074/jbc.M101866200
Dumitru CA, Gulbins E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene. 2006;25:5612–25.
pubmed: 16636669
doi: 10.1038/sj.onc.1209568
Carpinteiro A, Becker KA, Japtok L, Hessler G, Keitsch S, Pozgajova M, et al. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol Med. 2015;7:714–34.
pubmed: 25851537
pmcid: 4459814
doi: 10.15252/emmm.201404571
Rotolo J, Stancevic B, Zhang J, Hua G, Fuller J, Yin X, et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J Clin Invest. 2012;122:1786–90.
pubmed: 22466649
pmcid: 3336980
doi: 10.1172/JCI59920
Charruyer A, Grazide S, Bezombes C, Müller S, Laurent G, Jaffrézou JP. UV-C light induces raft-associated acid sphingomyelinase and JNK activation and translocation independently on a nuclear signal. J Biol Chem. 2005;280:19196–204.
pubmed: 15769735
doi: 10.1074/jbc.M412867200
Lang PA, Schenck M, Nicolay JP, Becker JU, Kempe DS, Lupescu A, et al. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med. 2007;13:164–70.
pubmed: 17259995
doi: 10.1038/nm1539
Grassmé H, Riehle A, Wilker B, Gulbins E. Rhinoviruses infect human epithelial cells via ceramide-enriched membrane platforms. J Biol Chem. 2005;280:26256–62.
pubmed: 15888438
doi: 10.1074/jbc.M500835200
Gulbins E, Kolesnick R. Raft ceramide in molecular medicine. Oncogene. 2003;22:7070–7.
pubmed: 14557812
doi: 10.1038/sj.onc.1207146
Sakuragawa N, Sakuragawa M, Kuwabara T, Pentchev PG, Barranger JA, Brady RO. Niemann-Pick disease experimental model: sphingomyelinase reduction induced by AY-9944. Science. 1977;196:317–9.
pubmed: 66749
doi: 10.1126/science.66749
Albouz S, Hauw JJ, Berwald-Netter Y, Boutry JM, Bourdon R, Baumann N. Tricyclic antidepressants induce sphingomyelinase deficiency in fibroblast and neuroblastoma cell cultures. Biomedicine. 1981;35:218–20.
pubmed: 6285997
Yoshida Y, Arimoto K, Sato M, Sakuragawa N, Arima M, Satoyoshi E. Reduction of acid sphingomyelinase activity in human fibroblasts induced by AY-9944 and other cationic amphiphilic drugs. J Biochem. 1985;98:1669–79.
pubmed: 2419314
doi: 10.1093/oxfordjournals.jbchem.a135438
Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, et al. Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model. J Med Chem. 2008;51:219–37.
pubmed: 18027916
doi: 10.1021/jm070524a
Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. Identification of novel functional inhibitors of acid sphingomyelinase. PLoS ONE. 2011;6:e23852.
pubmed: 21909365
pmcid: 3166082
doi: 10.1371/journal.pone.0023852
Trapp S, Rosania GR, Horobin RW, Kornhuber J. Quantitative modeling of selective lysosomal targeting for drug design. Eur Biophys J. 2008;37:1317–28.
pubmed: 18504571
pmcid: 2711917
doi: 10.1007/s00249-008-0338-4
Kölzer M, Werth N, Sandhoff K. Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett. 2004;559:96–8.
pubmed: 14960314
doi: 10.1016/S0014-5793(04)00033-X
Hurwitz R, Ferlinz K, Sandhoff K. The tricyclic antidepressants desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler. 1994;375:447–50.
pubmed: 7945993
doi: 10.1515/bchm3.1994.375.7.447
Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, et al. Functional inhibitors of acid sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem. 2010;26:9–20.
pubmed: 20502000
doi: 10.1159/000315101
Riethmüller J, Anthonysamy J, Serra E, Schwab M, Döring G, Gulbins E. Therapeutic efficacy and safety of amitriptyline in patients with cystic fibrosis. Cell Physiol Biochem. 2009;24:65–72.
pubmed: 19590194
doi: 10.1159/000227814
Nährlich L, Mainz JG, Adams C, Engel C, Herrmann G, Icheva V, et al. Therapy of CF-patients with amitriptyline and placebo - a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study. Cell Physiol Biochem. 2013;31:505–12.
pubmed: 23572075
doi: 10.1159/000350071
Cassano GB, Sjostrand SE, Hansson E. Distribution and fate of C
pubmed: 5892343
doi: 10.1007/BF00405356
Hilberg T, Mørland J, Bjørneboe A. Postmortem release of amitriptyline from the lungs; a mechanism of postmortem drug redistribution. Forensic Sci Int. 1994;64:47–55.
pubmed: 8157229
doi: 10.1016/0379-0738(94)90241-0
Bynum ND, Poklis JL, Gaffney-Kraft M, Garside D, Ropero-Miller JD. Postmortem distribution of tramadol, amitriptyline, and their metabolites in a suicidal overdose. J Anal Toxicol. 2005;29:401–6.
pubmed: 16105270
doi: 10.1093/jat/29.5.401
Johnson RD, Lewis RJ, Angier MK. The distribution of fluoxetine in human fluids and tissues. J Anal Toxicol. 2007;31:409–14.
pubmed: 17725889
doi: 10.1093/jat/31.7.409
Kornhuber J, Weigmann H, Rörich J, Wiltfang J, Bleich S, Meineke I, et al. Region specific distribution of levomepromazine in the human brain. J Neural Transm. 2006;113:387–97.
pubmed: 15997416
doi: 10.1007/s00702-005-0331-3
Miller ME, Adhikary S, Kolokoltsov AA, Davey RA. Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection. J Virol. 2012;86:7473–83.
pubmed: 22573858
pmcid: 3416309
doi: 10.1128/JVI.00136-12
Avota E, Gulbins E, Schneider-Schaulies S. DC-SIGN mediated sphingomyelinase-activation and ceramide generation is essential for enhancement of viral uptake in dendritic cells. PLoS Pathog. 2011;7:e1001290.
pubmed: 21379338
pmcid: 3040670
doi: 10.1371/journal.ppat.1001290
Tani H, Shiokawa M, Kaname Y, Kambara H, Mori Y, Abe T, et al. Involvement of ceramide in the propagation of Japanese encephalitis virus. J Virol. 2010;84:2798–807.
pubmed: 20053738
pmcid: 2826033
doi: 10.1128/JVI.02499-09
Shivanna V, Kim Y, Chang KO. Ceramide formation mediated by acid sphingomyelinase facilitates endosomal escape of caliciviruses. Virology. 2015;483:218–28.
pubmed: 25985440
doi: 10.1016/j.virol.2015.04.022
Esen M, Schreiner B, Jendrossek V, Lang F, Fassbender K, Grassmé H, et al. Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis. 2001;6:431–9.
pubmed: 11595832
doi: 10.1023/A:1012445925628
Grassmé H, Gulbins E, Brenner B, Ferlinz K, Sandhoff K, Harzer K, et al. Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell. 1997;91:605–15.
pubmed: 9393854
doi: 10.1016/S0092-8674(00)80448-1
Hauck CR, Grassmé H, Bock J, Jendrossek V, Ferlinz K, Meyer TF, et al. Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett. 2000;478:260–6.
pubmed: 10930579
doi: 10.1016/S0014-5793(00)01851-2
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18:41–58.
pubmed: 30310233
doi: 10.1038/nrd.2018.168
Santos J, Brierley S, Gandhi MJ, Cohen MA, Moschella PC, Declan ABL. Repurposing therapeutics for potential treatment of SARS-CoV-2: a review. Viruses. 2020;12:1–19.
doi: 10.3390/v12070705
Matsuyama S, Nagata N, Shirato K, Kawase M, Takeda M, Taguchi F. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol. 2010;84:12658–64.
pubmed: 20926566
pmcid: 3004351
doi: 10.1128/JVI.01542-10
Carpinteiro A, Gripp B, Hoffmann M, Pohlmann S, Hoertel N, Edwards MJ, et al. Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells. J Biol Chem. 2021;296:1–12.
doi: 10.1016/j.jbc.2021.100701
Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 1999;18:5252–63.
pubmed: 10508159
pmcid: 1171596
doi: 10.1093/emboj/18.19.5252
Carpinteiro A, Edwards MJ, Hoffmann M, Kochs G, Gripp B, Weigang S, et al. Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells. Cell Rep Med. 2020;1:100142.
pubmed: 33163980
pmcid: 7598530
doi: 10.1016/j.xcrm.2020.100142
Schloer S, Brunotte L, Goretzko J, Mecate-Zambrano A, Korthals N, Gerke V, et al. Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect. 2020;9:2245–55.
pubmed: 32975484
pmcid: 7594754
doi: 10.1080/22221751.2020.1829082
Dechaumes A, Nekoua MP, Belouzard S, Sane F, Engelmann I, Dubuisson J, et al. Fluoxetine can inhibit SARS-CoV-2 in vitro. Microorganisms. 2021;9:2–10.
doi: 10.3390/microorganisms9020339
Zimniak M, Kirschner L, Hilpert H, Geiger N, Danov O, Oberwinkler H, et al. The serotonin reuptake inhibitor fluoxetine inhibits SARS-CoV-2 in human lung tissue. Sci Rep. 2021;11:5890.
pubmed: 33723270
pmcid: 7961020
doi: 10.1038/s41598-021-85049-0
Fred SM, Kuivanen S, Ugurlu H, Casarotto PC, Levanov L, Saksela K, et al. Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro. bioRxiv. 2021. https://doi.org/10.1101/2021.03.22.436379 .
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583:459–68.
pubmed: 32353859
pmcid: 7431030
doi: 10.1038/s41586-020-2286-9
Weston S, Coleman CM, Haupt R, Logue J, Matthews K, Li Y, et al. Broad anti-coronavirus activity of Food and Drug Administration-approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo. J Virol. 2020;94:1–13.
doi: 10.1128/JVI.01218-20
Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob Agents Chemother. 2020;64:1–9.
doi: 10.1128/AAC.00819-20
Touret F, Gilles M, Barral K, Nougairede A, van HJ, Decroly E, et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Sci Rep. 2020;10:13093.
pubmed: 32753646
pmcid: 7403393
doi: 10.1038/s41598-020-70143-6
Mirabelli C, Wotring JW, Zhang CJ, McCarty SM, Fursmidt R, Pretto CD, et al. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. Proc Natl Acad Sci USA. 2021;118:1–12.
doi: 10.1073/pnas.2105815118
Yuan S, Yin X, Meng X, Chan JF, Ye ZW, Riva L, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature. 2021;593:418–23.
pubmed: 33727703
doi: 10.1038/s41586-021-03431-4
Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014;58:4885–93.
pubmed: 24841273
pmcid: 4136000
doi: 10.1128/AAC.03036-14
de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van NS, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58:4875–84.
pubmed: 24841269
pmcid: 4136071
doi: 10.1128/AAC.03011-14
Liu Q, Xia S, Sun Z, Wang Q, Du L, Lu L, et al. Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry. Antimicrob Agents Chemother. 2015;59:742–4.
pubmed: 25331705
doi: 10.1128/AAC.03977-14
Choy KT, Wong AY, Kaewpreedee P, Sia SF, Chen D, Hui KPY, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antivir Res. 2020;178:104786.
pubmed: 32251767
doi: 10.1016/j.antiviral.2020.104786
Ianevski A, Yao R, Fenstad MH, Biza S, Zusinaite E, Reisberg T, et al. Potential antiviral options against SARS-CoV-2 infection. Viruses. 2020;12:1–19.
doi: 10.3390/v12060642
Yang CW, Peng TT, Hsu HY, Lee YZ, Wu SH, Lin WH, et al. Repurposing old drugs as antiviral agents for coronaviruses. Biomed J. 2020;43:368–74.
pubmed: 32563698
pmcid: 7245249
doi: 10.1016/j.bj.2020.05.003
Ke YY, Peng TT, Yeh TK, Huang WZ, Chang SE, Wu SH, et al. Artificial intelligence approach fighting COVID-19 with repurposing drugs. Biomed J. 2020;43:355–62.
pubmed: 32426387
pmcid: 7227517
doi: 10.1016/j.bj.2020.05.001
Hoertel N, Sánchez-Rico M, Vernet R, Beeker N, Jannot AS, Neuraz A, et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Mol Psychiatry. 2021. in press; https://doi.org/10.1038/s41380-021-01021-4 .
Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324:2292–2300.
pubmed: 33180097
pmcid: 7662481
doi: 10.1001/jama.2020.22760
Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of Coronavirus Disease 19. Open Forum Infect Dis. 2021;8:ofab050.
pubmed: 33623808
pmcid: 7888564
doi: 10.1093/ofid/ofab050
Hoertel N, Sánchez M, Vernet R, Beeker N, Neuraz A, Blanco C, et al. Association between hydroxyzine use and reduced mortality in patients hospitalized for Coronavirus Disease 2019: results from a multicenter observational study. MedRxiv. 2020. https://doi.org/10.1101/2020.10.23.20154302 .
Hoertel N, Sánchez-Rico M, Gulbins E, Kornhuber J, Carpinteiro A, Lenze E, et al. Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: an observational multicenter study. Clin Pharmacol Ther. 2021. https://doi.org/10.1002/cpt.2317 .
Hoertel N, Sánchez-Rico M, Gulbins E, Kornhuber J, Carpinteiro A, Abellán M, et al. Association between psychotropic medications functionally inhibiting acid sphingomyelinase and reduced risk of intubation or death among individuals with mental disorder and severe COVID-19: an observational study. MedRxiv. 2021. https://doi.org/10.1101/2021.02.18.21251997 .
Darquennes G, Le Corre P, Le Moine O, Loas G. Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and reduced risk of death in COVID-19 patients: a retrospective cohort study. Pharmaceuticals. 2021;14:1–11.
doi: 10.3390/ph14030226
Marín-Corral J, Rodríguez-Morató J, Gomez-Gomez A, Pascual-Guardia S, Muñoz-Bermúdez R, Salazar-Degracia A, et al. Metabolic signatures associated with severity in hospitalized COVID-19 patients. Int J Mol Sci. 2021;22:4794.
pubmed: 33946479
pmcid: 8124482
doi: 10.3390/ijms22094794
Khodadoust, M. Ceramide levels and COVID-19 respiratory distress, a causal relationship. Research Square. 2021. https://doi.org/10.21203/rs.3.rs-443020/v3 .
FDA. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine. 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and .
Axfors C, Schmitt AM, Janiaud P, Van’t Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021;12:2349.
pubmed: 33859192
pmcid: 8050319
doi: 10.1038/s41467-021-22446-z
Homewood CA, Warhurst DC, Peters W, Baggaley VC. Lysosomes, pH and the anti-malarial action of chloroquine. Nature. 1972;235:50–52.
pubmed: 4550396
doi: 10.1038/235050a0
Jaffrézou JP, Chen G, Durán GE, Muller C, Bordier C, Laurent G, et al. Inhibition of lysosomal acid sphingomyelinase by agents which reverse multidrug resistance. Biochim Biophys Acta. 1995;1266:1–8.
pubmed: 7718613
doi: 10.1016/0167-4889(94)00219-5
Teichgräber V, Ulrich M, Endlich N, Riethmüller J, Wilker B, de Oliveira-Munding CC, et al. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med. 2008;14:382–91.
pubmed: 18376404
doi: 10.1038/nm1748
Elojeimy S, Holman DH, Liu X, El-Zawahry A, Villani M, Cheng JC, et al. New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett. 2006;580:4751–6.
pubmed: 16901483
doi: 10.1016/j.febslet.2006.07.071
Ng TW, Ooi EM, Watts GF, Chan DC, Weir JM, Meikle PJ, et al. Dose-dependent effects of rosuvastatin on the plasma sphingolipidome and phospholipidome in the metabolic syndrome. J Clin Endocrinol Metab. 2014;99:E2335–E2340.
pubmed: 25140396
doi: 10.1210/jc.2014-1665
Israel A, Schäffer AA, Cicurel A, Cheng K, Sinha S, Schiff E, et al. Identification of drugs associated with reduced severity of COVID-19—a case-control study in a large population. Elife. 2021;10:1–14.
doi: 10.7554/eLife.68165
Rosen DA, Seki SM, Fernandez-Castaneda A, Beiter RM, Eccles JD, Woodfolk JA, et al. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11:eaau5266.
pubmed: 30728287
pmcid: 6936250
doi: 10.1126/scitranslmed.aau5266
Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, et al. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science. 2020;370:1–25.
doi: 10.1126/science.abe9403
Cobos EJ, Entrena JM, Nieto FR, Cendan CM, Del PE. Pharmacology and therapeutic potential of sigma
pubmed: 19587856
pmcid: 2701284
doi: 10.2174/157015908787386113
Omi T, Tanimukai H, Kanayama D, Sakagami Y, Tagami S, Okochi M, et al. Fluvoxamine alleviates ER stress via induction of sigma-1 receptor. Cell Death Dis. 2014;5:e1332.
pubmed: 25032855
pmcid: 4123092
doi: 10.1038/cddis.2014.301
Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharm. 2014;727:167–73.
doi: 10.1016/j.ejphar.2014.01.064
WHO. Therapeutics and COVID-19: living guideline. 6-7-2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.2 .
Schloer S, Brunotte L, Mecate-Zambrano A, Zheng S, Tang J, Ludwig S, et al. Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharm. 2021;178:2339–50.
doi: 10.1111/bph.15418
Drobnik W, Liebisch G, Audebert FX, Fröhlich D, Glück T, Vogel P, et al. Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res. 2003;44:754–61.
pubmed: 12562829
doi: 10.1194/jlr.M200401-JLR200
Wong ML, Xie B, Beatini N, Phu P, Marathe S, Johns A, et al. Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis. Proc Natl Acad Sci USA. 2000;97:8681–6.
pubmed: 10890909
pmcid: 27008
doi: 10.1073/pnas.150098097
Claus RA, Bunck AC, Bockmeyer CL, Brunkhorst FM, Lösche W, Kinscherf R, et al. Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. FASEB J. 2005;19:1719–21.
pubmed: 16051685
doi: 10.1096/fj.04-2842fje
Kornhuber J, Rhein C, Müller CP, Mühle C. Secretory sphingomyelinase in health and disease. Biol Chem. 2015;396:707–36.
pubmed: 25803076
doi: 10.1515/hsz-2015-0109
Peng H, Li C, Kadow S, Henry BD, Steinmann J, Becker KA, et al. Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis. J Mol Med. 2015;93:675–89.
pubmed: 25616357
doi: 10.1007/s00109-014-1246-y
Chung HY, Witt CJ, Jbeily N, Hurtado-Oliveros J, Giszas B, Lupp A, et al. Acid sphingomyelinase inhibition prevents development of sepsis sequelae in the murine liver. Sci Rep. 2017;7:12348.
pubmed: 28955042
pmcid: 5617833
doi: 10.1038/s41598-017-11837-2
Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330–41.
pubmed: 32876694
doi: 10.1001/jama.2020.17023
Hoertel N, Sánchez-Rico M, Vernet R, Beeker N, Neuraz A, Alvarado JM, et al. Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: a multicentre retrospective observational study. Br J Clin Pharmacol. 2021;87:3766–75.
pubmed: 33608891
doi: 10.1111/bcp.14784
Tleyjeh IM, Kashour Z, Damlaj M, Riaz M, Tlayjeh H, Altannir M, et al. Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic review and meta-analysis. Clin Microbiol Infect. 2021;27:215–27.
pubmed: 33161150
doi: 10.1016/j.cmi.2020.10.036
Perry DM, Newcomb B, Adada M, Wu BX, Roddy P, Kitatani K, et al. Defining a role for acid sphingomyelinase in the p38/interleukin-6 pathway. J Biol Chem. 2014;289:22401–12.
pubmed: 24951586
pmcid: 4139247
doi: 10.1074/jbc.M114.589648
Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell. 1992;71:765–76.
pubmed: 1330325
doi: 10.1016/0092-8674(92)90553-O
Köhler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: Systematic review and meta-analysis. Mol Neurobiol. 2018;55:4195–206.
pubmed: 28612257
Vozella V, Basit A, Piras F, Realini N, Armirotti A, Bossu P, et al. Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study. Aging. 2019;11:73–88.
pubmed: 30620722
pmcid: 6339790
doi: 10.18632/aging.101719
Park MH, Lee JK, Park KH, Jung IK, Kim KT, Lee YS, et al. Vascular and neurogenic rejuvenation in aging mice by modulation of ASM. Neuron. 2018;100:167–82.
pubmed: 30269989
doi: 10.1016/j.neuron.2018.09.010
Babenko NA, Garkavenko VV, Storozhenko GV, Timofiychuk OA. Role of acid sphingomyelinase in the age-dependent dysregulation of sphingolipids turnover in the tissues of rats. Gen Physiol Biophys. 2016;35:195–205.
pubmed: 26830134
doi: 10.4149/gpb_2015046
Couttas TA, Kain N, Tran C, Chatterton Z, Kwok JB, Don AS. Age-dependent changes to sphingolipid balance in the human hippocampus are gender-specific and may sensitize to neurodegeneration. J Alzheimers Dis. 2018;63:503–14.
pubmed: 29660940
doi: 10.3233/JAD-171054
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101:2070–5.
pubmed: 14970312
pmcid: 357053
doi: 10.1073/pnas.0305799101
Spijkers LJA, van den Akker RFP, Janssen BJA, Debets JJ, De Mey JGR, Stroes ESG, et al. Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide. PLoS ONE. 2011;6:e21817.
pubmed: 21818267
pmcid: 3139577
doi: 10.1371/journal.pone.0021817
Boini KM, Zhang C, Xia M, Poklis JL, Li PL. Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet. J Pharm Exp Ther. 2010;334:839–46.
doi: 10.1124/jpet.110.168815
Wang J, Pendurthi UR, Rao LVM. Sphingomyelin encrypts tissue factor: ATP-induced activation of A-SMase leads to tissue factor decryption and microvesicle shedding. Blood Adv. 2017;1:849–62.
pubmed: 28758160
pmcid: 5531194
doi: 10.1182/bloodadvances.2016003947
Wang J, Pendurthi UR, Rao LVM. Acid sphingomyelinase plays a critical role in LPS- and cytokine-induced tissue factor procoagulant activity. Blood. 2019;134:645–55.
pubmed: 31262782
pmcid: 6695563
doi: 10.1182/blood.2019001400
Wang J, Pendurthi UR, Yi G, Rao VM. SARS-CoV-2 infection induces the activation of tissue factor-mediated coagulation via activation of acid sphingomyelinase. Blood. 2021;138:344–9.
pubmed: 34075401
pmcid: 8172270
doi: 10.1182/blood.2021010685
Hoertel N, Sánchez-Rico M, Cougoule C, Gulbins E, Kornhuber J, Carpinteiro A, et al. Repurposing antidepressants inhibiting the acid sphingomyelinase/ceramide system against COVID-19: current evidence and potential mechanisms. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-021-01254-3 .