1887

Abstract

There is growing evidence of the influence of sphingosine kinase (SK) enzymes on viral infection. Here, the role of sphingosine kinase 2 (SK2), an isoform of SK prominent in the brain, was defined during dengue virus (DENV) infection. Chemical inhibition of SK2 activity using two different SK2 inhibitors, ABC294640 and K145, had no effect on DENV infection in human cells in vitro. In contrast, DENV infection was restricted in SK2 immortalized mouse embryonic fibroblasts (iMEFs) with reduced induction of IFN-β mRNA and protein, and mRNA for the IFN-stimulated genes (ISGs) viperin, IFIT1, IRF7 and CXCL10 in DENV-infected SK2 compared to WT iMEFs. Intracranial (ic) DENV injection in C57BL/6 SK2 mice induced body weight loss earlier than in WT mice but DENV RNA levels were comparable in the brain. Neither SK1 mRNA or sphingosine-1-phosphate (S1P) levels were altered following ic DENV infection in WT or SK2 mice but brain S1P levels were reduced in all SK2 mice, independent of DENV infection. CD8 mRNA was induced in the brains of both DENV-infected WT and SK2 mice, suggesting normal CD8+ T-cell infiltration into the DENV-infected brain independent of SK2 or S1P. Thus, although SK2 may be important for replication of some viruses SK2 activity does not affect DENV infection in vitro and SK2 or S1P levels do not influence DENV infection or T-cell infiltration in the context of infection in the brain.

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2019-03-14
2024-12-10
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References

  1. Alvarez SE, Milstien S, Spiegel S. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab 2007; 18:300–307 [View Article][PubMed]
    [Google Scholar]
  2. Pitson SM. Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci 2011; 36:97–107 [View Article][PubMed]
    [Google Scholar]
  3. Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer 2010; 10:489–503 [View Article][PubMed]
    [Google Scholar]
  4. Pyne S, Lee SC, Long J, Pyne NJ. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal 2009; 21:14–21 [View Article][PubMed]
    [Google Scholar]
  5. Neubauer HA, Pitson SM. Roles, regulation and inhibitors of sphingosine kinase 2. FEBS J 2013; 280:5317–5336 [View Article][PubMed]
    [Google Scholar]
  6. Siow DL, Anderson CD, Berdyshev EV, Skobeleva A, Natarajan V et al. Sphingosine kinase localization in the control of sphingolipid metabolism. Adv Enzyme Regul 2011; 51:229–244 [View Article][PubMed]
    [Google Scholar]
  7. Neubauer HA, Tea MN, Zebol JR, Gliddon BL, Stefanidis C et al. Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene 2019; 38:1151–1165 [View Article][PubMed]
    [Google Scholar]
  8. Pyne NJ, Adams DR, Pyne S. Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol Sci 2017; 38:581–591 [View Article][PubMed]
    [Google Scholar]
  9. Pitman MR, Costabile M, Pitson SM. Recent advances in the development of sphingosine kinase inhibitors. Cell Signal 2016; 28:1349–1363 [View Article][PubMed]
    [Google Scholar]
  10. French KJ, Zhuang Y, Maines LW, Gao P, Wang W et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther 2010; 333:129–139 [View Article][PubMed]
    [Google Scholar]
  11. Liu K, Guo TL, Hait NC, Allegood J, Parikh HI et al. Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a selective sphingosine kinase-2 inhibitor and anticancer agent. PLoS One 2013; 8:e56471 [View Article][PubMed]
    [Google Scholar]
  12. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW et al. The global distribution and burden of dengue. Nature 2013; 496:504–507 [View Article][PubMed]
    [Google Scholar]
  13. WHO Global Strategy for Dengue Prevention and Control, 2012-2020 Geneva: World Health Organization; 2012
    [Google Scholar]
  14. Katzelnick LC, Coloma J, Harris E. Dengue: knowledge gaps, unmet needs, and research priorities. Lancet Infect Dis 2017; 17:e88e100 [View Article][PubMed]
    [Google Scholar]
  15. Maceyka M, Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature 2014; 510:58–67 [View Article][PubMed]
    [Google Scholar]
  16. Carr JM, Mahalingam S, Bonder CS, Pitson SM. Sphingosine kinase 1 in viral infections. Rev Med Virol 2013; 23:73–84 [View Article][PubMed]
    [Google Scholar]
  17. Schneider-Schaulies J, Schneider-Schaulies S. Sphingolipids in viral infection. Biol Chem 2015; 396:585–595 [View Article][PubMed]
    [Google Scholar]
  18. Machesky NJ, Zhang G, Raghavan B, Zimmerman P, Kelly SL et al. Human cytomegalovirus regulates bioactive sphingolipids. J Biol Chem 2008; 283:26148–26160 [View Article][PubMed]
    [Google Scholar]
  19. Seo YJ, Blake C, Alexander S, Hahm B. Sphingosine 1-phosphate-metabolizing enzymes control influenza virus propagation and viral cytopathogenicity. J Virol 2010; 84:8124–8131 [View Article][PubMed]
    [Google Scholar]
  20. Vijayan M, Seo YJ, Pritzl CJ, Squires SA, Alexander S et al. Sphingosine kinase 1 regulates measles virus replication. Virology 2014; 450-451:55–63 [View Article][PubMed]
    [Google Scholar]
  21. Yamane D, Zahoor MA, Mohamed YM, Azab W, Kato K et al. Inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis. J Biol Chem 2009; 284:13648–13659 [View Article][PubMed]
    [Google Scholar]
  22. Carr JM, Kua T, Clarke JN, Calvert JK, Zebol JR et al. Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3' untranslated region of dengue virus type-2 RNA. J Gen Virol 2013; 94:2437–2448 [View Article][PubMed]
    [Google Scholar]
  23. Calvert JK, Helbig KJ, Dimasi D, Cockshell M, Beard MR et al. Dengue virus infection of primary endothelial cells induces innate immune responses, changes in endothelial cells function and is restricted by interferon-stimulated responses. J Interferon Cytokine Res 2015; 35:654–665 [View Article][PubMed]
    [Google Scholar]
  24. Aloia AL, Calvert JK, Clarke JN, Davies LT, Helbig KJ et al. Investigation of sphingosine kinase 1 in interferon responses during dengue virus infection. Clin Transl Immunology 2017; 6:e151 [View Article][PubMed]
    [Google Scholar]
  25. Clarke JN, Davies LK, Calvert JK, Gliddon BL, Al Shujari WH et al. Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses. J Gen Virol 2016; 97:95–109 [View Article][PubMed]
    [Google Scholar]
  26. Dai L, Plaisance-Bonstaff K, Voelkel-Johnson C, Smith CD, Ogretmen B et al. Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells. PLoS One 2014; 9:e102314 [View Article][PubMed]
    [Google Scholar]
  27. Yamane D, Mcgivern DR, Wauthier E, Yi M, Madden VJ et al. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med 2014; 20:927–935 [View Article]
    [Google Scholar]
  28. Reid SP, Tritsch SR, Kota K, Chiang CY, Dong L et al. Sphingosine kinase 2 is a chikungunya virus host factor co-localized with the viral replication complex. Emerg Microbes Infect 2015; 4:1–9 [View Article][PubMed]
    [Google Scholar]
  29. Morchang A, Lee RCH, Yenchitsomanus PT, Sreekanth GP, Noisakran S et al. RNAi screen reveals a role of SPHK2 in dengue virus-mediated apoptosis in hepatic cell lines. PLoS One 2017; 12:e0188121 [View Article][PubMed]
    [Google Scholar]
  30. Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005; 25:11113–11121 [View Article][PubMed]
    [Google Scholar]
  31. Gualano RC, Pryor MJ, Cauchi MR, Wright PJ, Davidson AD. Identification of a major determinant of mouse neurovirulence of dengue virus type 2 using stably cloned genomic-length cDNA. J Gen Virol 1998; 79:437–446 [View Article][PubMed]
    [Google Scholar]
  32. Wati S, Li P, Burrell CJ, Carr JM. Dengue virus (DV) replication in monocyte-derived macrophages is not affected by tumor necrosis factor alpha (TNF-alpha), and DV infection induces altered responsiveness to TNF-alpha stimulation. J Virol 2007; 81:10161–10171 [View Article][PubMed]
    [Google Scholar]
  33. Al-Shujairi WH, Clarke JN, Davies LT, Alsharifi M, Pitson SM et al. Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways. PLoS One 2017; 12:e0169814 [View Article][PubMed]
    [Google Scholar]
  34. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3:1101–1108 [View Article][PubMed]
    [Google Scholar]
  35. Pitman MR, Powell JA, Coolen C, Moretti PA, Zebol JR et al. A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties. Oncotarget 2015; 6:7065–7083 [View Article][PubMed]
    [Google Scholar]
  36. Leclercq TM, Moretti PA, Vadas MA, Pitson SM. Eukaryotic elongation factor 1A interacts with sphingosine kinase and directly enhances its catalytic activity. J Biol Chem 2008; 283:9606–9614 [View Article][PubMed]
    [Google Scholar]
  37. Ansarah-Sobrinho C, Nelson S, Jost CA, Whitehead SS, Pierson TC. Temperature-dependent production of pseudoinfectious dengue reporter virus particles by complementation. Virology 2008; 381:67–74 [View Article][PubMed]
    [Google Scholar]
  38. Wallington-Beddoe CT, Bennett MK, Vandyke K, Davies L, Zebol JR et al. Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress. Oncotarget 2017; 8:43602–43616 [View Article][PubMed]
    [Google Scholar]
  39. Baeyens A, Fang V, Chen C, Schwab SR. Exit Strategies: S1P signaling and T cell migration. Trends Immunol 2015; 36:778–787 [View Article][PubMed]
    [Google Scholar]
  40. Seo YJ, Pritzl CJ, Vijayan M, Bomb K, Mcclain ME et al. Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection. PLoS One 2013; 8:e75005 [View Article][PubMed]
    [Google Scholar]
  41. Xia C, Seo YJ, Studstill CJ, Vijayan M, Wolf JJ et al. Transient inhibition of sphingosine kinases confers protection to influenza A virus infected mice. Antiviral Res 2018; 158:171–177 [View Article][PubMed]
    [Google Scholar]
  42. Oldstone MB, Rosen H. Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1-phosphate agonist molecule. Curr Top Microbiol Immunol 2014; 378:129–147 [View Article][PubMed]
    [Google Scholar]
  43. Jordan TX, Randall G. Dengue virus activates the AMP Kinase-mTOR axis to stimulate a proviral lipophagy. J Virol 2017; 91: [View Article][PubMed]
    [Google Scholar]
  44. Zhang J, Lan Y, Li MY, Lamers MM, Fusade-Boyer M et al. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production. Cell Host Microbe 2018; 23:819–831 [View Article][PubMed]
    [Google Scholar]
  45. Gullberg RC, Steel JJ, Pujari V, Rovnak J, Crick DC et al. Stearoly-CoA desaturase 1 differentiates early and advanced dengue virus infections and determines virus particle infectivity. PLoS Pathog 2018; 14:e1007261 [View Article][PubMed]
    [Google Scholar]
  46. Cui L, Hou J, Fang J, Lee YH, Costa VV et al. Serum metabolomics investigation of humanized mouse model of dengue virus infection. J Virol 2017; 91: [View Article][PubMed]
    [Google Scholar]
  47. Aktepe TE, Pham H, Mackenzie JM. Differential utilisation of ceramide during replication of the flaviviruses West Nile and dengue virus. Virology 2015; 484:241–250 [View Article][PubMed]
    [Google Scholar]
  48. Giacobbi NS, Gupta T, Coxon AT, Pipas JM. Polyomavirus T antigens activate an antiviral state. Virology 2015; 476:377–385 [View Article][PubMed]
    [Google Scholar]
  49. Canlas J, Holt P, Carroll A, Rix S, Ryan P et al. Sphingosine kinase 2-deficiency mediated changes in spinal pain processing. Front Mol Neurosci 2015; 8:29 [View Article][PubMed]
    [Google Scholar]
  50. Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 2004; 279:52487–52492 [View Article][PubMed]
    [Google Scholar]
  51. Kharel Y, Lee S, Snyder AH, Sheasley-O'Neill SL, Morris MA et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 2005; 280:36865–36872 [View Article][PubMed]
    [Google Scholar]
  52. Sensken SC, Bode C, Nagarajan M, Peest U, Pabst O et al. Redistribution of sphingosine 1-phosphate by sphingosine kinase 2 contributes to lymphopenia. J Immunol 2010; 184:4133–4142 [View Article][PubMed]
    [Google Scholar]
  53. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 2007; 8:1295–1301 [View Article][PubMed]
    [Google Scholar]
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