1887

Abstract

Sphingosine kinase (SK) 1 is a host kinase that enhances some viral infections. Here we investigated the ability of SK1 to modulate dengue virus (DENV) infection . Overexpression of SK1 did not alter DENV infection; however, targeting SK1 through chemical inhibition resulted in reduced DENV RNA and infectious virus release. DENV infection of SK1 murine embryonic fibroblasts (MEFs) resulted in inhibition of infection in an immortalized line (iMEF) but enhanced infection in primary MEFs (1°MEFs). Global cellular gene expression profiles showed expected innate immune mRNA changes in DENV-infected WT but no induction of these responses in SK1 iMEFs. Reverse transciption PCR demonstrated a low-level induction of IFN-β and poor induction of mRNA for the interferon-stimulated genes (ISGs) viperin, IFIT1 and CXCL10 in DENV-infected SK1 compared with WT iMEFs. Similarly, reduced induction of ISGs was observed in SK1 1°MEFs, even in the face of high-level DENV replication. In both iMEFs and 1°MEFs, DENV infection induced production of IFN-β protein. Additionally, higher basal levels of antiviral factors (IRF7, CXCL10 and OAS1) were observed in uninfected SK1 iMEFs but not 1°MEFs. This suggests that, in this single iMEF line, lack of SK1 upregulates the basal levels of factors that may protect cells against DENV infection. More importantly, regardless of the levels of DENV replication, all cells that lacked SK1 produced IFN-β but were refractory to induction of ISGs such as viperin, IFIT1 and CXCL10. Based on these findings, we propose new roles for SK1 in affecting innate responses that regulate susceptibility to DENV infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000334
2016-01-01
2019-12-12
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/1/95.html?itemId=/content/journal/jgv/10.1099/jgv.0.000334&mimeType=html&fmt=ahah

References

  1. Adada M. M., Orr-Gandy K. A., Snider A. J., Canals D., Hannun Y. A., Obeid L. M., Clarke C. J.. 2013; Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor κB activation. J Biol Chem288:27667–27679 [CrossRef][PubMed]
    [Google Scholar]
  2. Allende M. L., Sasaki T., Kawai H., Olivera A., Mi Y., van Echten-Deckert G., Hajdu R., Rosenbach M., Keohane C. A., other authors. 2004; Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem279:52487–52492 [CrossRef][PubMed]
    [Google Scholar]
  3. Alvarez S. E., Harikumar K. B., Hait N. C., Allegood J., Strub G. M., Kim E. Y., Maceyka M., Jiang H., Luo C., other authors. 2010; Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature465:1084–1088 [CrossRef][PubMed]
    [Google Scholar]
  4. Blackwell J. L., Brinton M. A.. 1997; Translation elongation factor-1 alpha interacts with the 3′ stem-loop region of West Nile virus genomic RNA. J Virol71:6433–6444[PubMed]
    [Google Scholar]
  5. Calvert J. K., Helbig K. J., Dimasi D., Cockshell M., Beard M. R., Pitson S. M., Bonder C. S., Carr J. M.. 2015; 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 Res35:654–665 [CrossRef][PubMed]
    [Google Scholar]
  6. Carr J. M., Kua T., Clarke J. N., Calvert J. K., Zebol J. R., Beard M. R., Pitson S. M.. 2013a; 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 Virol94:2437–2448 [CrossRef][PubMed]
    [Google Scholar]
  7. Carr J. M., Mahalingam S., Bonder C. S., Pitson S. M.. 2013b; Sphingosine kinase 1 in viral infections. Rev Med Virol23:73–84 [CrossRef][PubMed]
    [Google Scholar]
  8. Chen H. W., King K., Tu J., Sanchez M., Luster A. D., Shresta S.. 2013; The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus. J Immunol191:4194–4201 [CrossRef][PubMed]
    [Google Scholar]
  9. Conceição T. M., El-Bacha T., Villas-Bôas C. S., Coello G., Ramírez J., Montero-Lomeli M., Da Poian A. T.. 2010; Gene expression analysis during dengue virus infection in HepG2 cells reveals virus control of innate immune response. J Infect60:65–75 [CrossRef][PubMed]
    [Google Scholar]
  10. Davis W. G., Blackwell J. L., Shi P. Y., Brinton M. A.. 2007; Interaction between the cellular protein eEF1A and the 3′-terminal stem-loop of West Nile virus genomic RNA facilitates viral minus-strand RNA synthesis. J Virol81:10172–10187 [CrossRef][PubMed]
    [Google Scholar]
  11. Fink J., Gu F., Ling L., Tolfvenstam T., Olfat F., Chin K. C., Aw P., George J., Kuznetsov V. A., other authors. 2007; Host gene expression profiling of dengue virus infection in cell lines and patients. PLoS Negl Trop Dis1:e86 [CrossRef][PubMed]
    [Google Scholar]
  12. Giacobbi N. S., Gupta T., Coxon A. T., Pipas J. M.. 2015; Polyomavirus T antigens activate an antiviral state. Virology476:377–385 [CrossRef][PubMed]
    [Google Scholar]
  13. Gualano R. C., Pryor M. J., Cauchi M. R., Wright P. J., Davidson A. D.. 1998; Identification of a major determinant of mouse neurovirulence of dengue virus type 2 using stably cloned genomic-length cDNA. J Gen Virol79:437–446 [CrossRef][PubMed]
    [Google Scholar]
  14. Guzman M. G., Halstead S. B., Artsob H., Buchy P., Farrar J., Gubler D. J., Hunsperger E., Kroeger A., Margolis H. S., other authors. 2010; Dengue: a continuing global threat. Nat Rev Microbiol8:S7–S16 [CrossRef][PubMed]
    [Google Scholar]
  15. Halstead S. B.. 1989; Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis11:(Suppl. 4)S830–S839 [CrossRef][PubMed]
    [Google Scholar]
  16. Halstead S. B., Mahalingam S., Marovich M. A., Ubol S., Mosser D. M.. 2010; Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis10:712–722 [CrossRef][PubMed]
    [Google Scholar]
  17. Harikumar K. B., Yester J. W., Surace M. J., Oyeniran C., Price M. M., Huang W. C., Hait N. C., Allegood J. C., Yamada A., other authors. 2014; K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5. Nat Immunol15:231–238 [CrossRef][PubMed]
    [Google Scholar]
  18. Helbig K. J., Carr J. M., Calvert J. K., Wati S., Clarke J. N., Eyre N. S., Narayana S. K., Fiches G. N., McCartney E. M., Beard M. R.. 2013; Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin. PLoS Negl Trop Dis7:e2178 [CrossRef][PubMed]
    [Google Scholar]
  19. Jiang D., Weidner J. M., Qing M., Pan X. B., Guo H., Xu C., Zhang X., Birk A., Chang J., other authors. 2010; Identification of five interferon-induced cellular proteins that inhibit West Nile virus and dengue virus infections. J Virol84:8332–8341 [CrossRef][PubMed]
    [Google Scholar]
  20. Leclercq T. M., Pitson S. M.. 2006; Cellular signalling by sphingosine kinase and sphingosine 1-phosphate. IUBMB Life58:467–472 [CrossRef][PubMed]
    [Google Scholar]
  21. Leclercq T. M., Moretti P. A., Vadas M. A., Pitson S. M.. 2008; Eukaryotic elongation factor 1A interacts with sphingosine kinase and directly enhances its catalytic activity. J Biol Chem283:9606–9614 [CrossRef][PubMed]
    [Google Scholar]
  22. Leclercq T. M., Moretti P. A., Pitson S. M.. 2011; Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis. Oncogene30:372–378 [CrossRef][PubMed]
    [Google Scholar]
  23. Liew K. J., Chow V. T.. 2006; Microarray and real-time RT-PCR analyses of a novel set of differentially expressed human genes in ECV304 endothelial-like cells infected with dengue virus type 2. J Virol Methods131:47–57 [CrossRef][PubMed]
    [Google Scholar]
  24. Lin R. J., Yu H. P., Chang B. L., Tang W. C., Liao C. L., Lin Y. L.. 2009; Distinct antiviral roles for human 2′,5′-oligoadenylate synthetase family members against dengue virus infection. J Immunol183:8035–8043 [CrossRef][PubMed]
    [Google Scholar]
  25. Maceyka M., Milstien S., Spiegel S.. 2009; Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling. J Lipid Res50:S272–S276 [CrossRef][PubMed]
    [Google Scholar]
  26. Machesky N. J., Zhang G., Raghavan B., Zimmerman P., Kelly S. L., Merrill A. H. Jr, Waldman W. J., Van Brocklyn J. R., Trgovcich J.. 2008; Human cytomegalovirus regulates bioactive sphingolipids. J Biol Chem283:26148–26160 [CrossRef][PubMed]
    [Google Scholar]
  27. Marsolais D., Hahm B., Walsh K. B., Edelmann K. H., McGavern D., Hatta Y., Kawaoka Y., Rosen H., Oldstone M. B.. 2009; A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc Natl Acad Sci U S A106:1560–1565 [CrossRef][PubMed]
    [Google Scholar]
  28. Mizugishi K., Inoue T., Hatayama H., Bielawski J., Pierce J. S., Sato Y., Takaori-Kondo A., Konishi I., Yamashita K.. 2015; Sphingolipid pathway regulates innate immune responses at the fetomaternal interface during pregnancy. J Biol Chem290:2053–2068 [CrossRef][PubMed]
    [Google Scholar]
  29. Monick M. M., Cameron K., Powers L. S., Butler N. S., McCoy D., Mallampalli R. K., Hunninghake G. W.. 2004; Sphingosine kinase mediates activation of extracellular signal-related kinase and Akt by respiratory syncytial virus. Am J Respir Cell Mol Biol30:844–852 [CrossRef][PubMed]
    [Google Scholar]
  30. Nascimento E. J., Hottz E. D., Garcia-Bates T. M., Bozza F., Marques E. T. Jr, Barratt-Boyes S. M.. 2014; Emerging concepts in dengue pathogenesis: interplay between plasmablasts, platelets, and complement in triggering vasculopathy. Crit Rev Immunol34:227–240 [CrossRef][PubMed]
    [Google Scholar]
  31. Neubauer H. A., Pitson S. M.. 2013; Roles, regulation and inhibitors of sphingosine kinase 2. FEBS J280:5317–5336 [CrossRef][PubMed]
    [Google Scholar]
  32. Oldstone M. B., Rosen H.. 2014; 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 Immunol378:129–147[PubMed]
    [Google Scholar]
  33. Oskeritzian C. A., Alvarez S. E., Hait N. C., Price M. M., Milstien S., Spiegel S.. 2008; Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood111:4193–4200 [CrossRef][PubMed]
    [Google Scholar]
  34. Paugh S. W., Paugh B. S., Rahmani M., Kapitonov D., Almenara J. A., Kordula T., Milstien S., Adams J. K., Zipkin R. E., other authors. 2008; A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood112:1382–1391 [CrossRef][PubMed]
    [Google Scholar]
  35. Pchejetski D., Nunes J., Coughlan K., Lall H., Pitson S. M., Waxman J., Sumbayev V. V.. 2011; The involvement of sphingosine kinase 1 in LPS-induced Toll-like receptor 4-mediated accumulation of HIF-1α protein, activation of ASK1 and production of the pro-inflammatory cytokine IL-6. Immunol Cell Biol89:268–274 [CrossRef][PubMed]
    [Google Scholar]
  36. Perelygin A. A., Scherbik S. V., Zhulin I. B., Stockman B. M., Li Y., Brinton M. A.. 2002; Positional cloning of the murine flavivirus resistance gene. Proc Natl Acad Sci U S A99:9322–9327 [CrossRef][PubMed]
    [Google Scholar]
  37. Pham D. H., Powell J. A., Gliddon B. L., Moretti P. A., Tsykin A., Van der Hoek M., Kenyon R., Goodall G. J., Pitson S. M.. 2014; Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1. Oncogene33:5559–5568 [CrossRef][PubMed]
    [Google Scholar]
  38. Pitman M. R., Pham D. H., Pitson S. M.. 2012; Isoform-selective assays for sphingosine kinase activity. Methods Mol Biol874:21–31 [CrossRef][PubMed]
    [Google Scholar]
  39. Pitson S. M.. 2011; Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci36:97–107 [CrossRef][PubMed]
    [Google Scholar]
  40. Pitson S. M., Moretti P. A., Zebol J. R., Xia P., Gamble J. R., Vadas M. A., D'Andrea R. J., Wattenberg B. W.. 2000; Expression of a catalytically inactive sphingosine kinase mutant blocks agonist-induced sphingosine kinase activation. A dominant-negative sphingosine kinase. J Biol Chem275:33945–33950 [CrossRef][PubMed]
    [Google Scholar]
  41. Pitson S. M., Moretti P. A., Zebol J. R., Lynn H. E., Xia P., Vadas M. A., Wattenberg B. W.. 2003; Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J22:5491–5500 [CrossRef][PubMed]
    [Google Scholar]
  42. Pitson S. M., Xia P., Leclercq T. M., Moretti P. A., Zebol J. R., Lynn H. E., Wattenberg B. W., Vadas M. A.. 2005; Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med201:49–54 [CrossRef][PubMed]
    [Google Scholar]
  43. Pyne S., Bittman R., Pyne N. J.. 2011; Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules. Cancer Res71:6576–6582 [CrossRef][PubMed]
    [Google Scholar]
  44. Rosen H., Germana Sanna M., Gonzalez-Cabrera P. J., Roberts E.. 2014; The organization of the sphingosine 1-phosphate signaling system. Curr Top Microbiol Immunol378:1–21[PubMed]
    [Google Scholar]
  45. Seo Y. J., Blake C., Alexander S., Hahm B.. 2010; Sphingosine 1-phosphate-metabolizing enzymes control influenza virus propagation and viral cytopathogenicity. J Virol84:8124–8131 [CrossRef][PubMed]
    [Google Scholar]
  46. Seo Y. J., Alexander S., Hahm B.. 2011; Does cytokine signaling link sphingolipid metabolism to host defense and immunity against virus infections?. Cytokine Growth Factor Rev22:55–61 [CrossRef][PubMed]
    [Google Scholar]
  47. Seo Y. J., Pritzl C. J., Vijayan M., Bomb K., McClain M. E., Alexander S., Hahm B.. 2013; 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 One8:e75005 [CrossRef][PubMed]
    [Google Scholar]
  48. Simmons C. P., Farrar J. J., van Vinh Chau N., Wills B.. 2012; Dengue. N Engl J Med366:1423–1432 [CrossRef][PubMed]
    [Google Scholar]
  49. Spiegel S., Milstien S.. 2011; The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol11:403–415 [CrossRef][PubMed]
    [Google Scholar]
  50. Suthar M. S., Aguirre S., Fernandez-Sesma A.. 2013; Innate immune sensing of flaviviruses. PLoS Pathog9:e1003541 [CrossRef][PubMed]
    [Google Scholar]
  51. Vijayan M., Seo Y. J., Pritzl C. J., Squires S. A., Alexander S., Hahm B.. 2014; Sphingosine kinase 1 regulates measles virus replication. Virology450-451:55–63 [CrossRef][PubMed]
    [Google Scholar]
  52. Walsh K. B., Teijaro J. R., Wilker P. R., Jatzek A., Fremgen D. M., Das S. C., Watanabe T., Hatta M., Shinya K., other authors. 2011; Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci U S A108:12018–12023 [CrossRef][PubMed]
    [Google Scholar]
  53. Walsh K. B., Teijaro J. R., Brock L. G., Fremgen D. M., Collins P. L., Rosen H., Oldstone M. B.. 2014; Animal model of respiratory syncytial virus: CD8+T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. J Virol88:6281–6293 [CrossRef][PubMed]
    [Google Scholar]
  54. Warke R. V., Xhaja K., Martin K. J., Fournier M. F., Shaw S. K., Brizuela N., de Bosch N., Lapointe D., Ennis F. A., other authors. 2003; Dengue virus induces novel changes in gene expression of human umbilical vein endothelial cells. J Virol77:11822–11832 [CrossRef][PubMed]
    [Google Scholar]
  55. Wati S., Rawlinson S. M., Ivanov R. A., Dorstyn L., Beard M. R., Jans D. A., Pitson S. M., Burrell C. J., Li P., Carr J. M.. 2011; Tumour necrosis factor alpha (TNF-α) stimulation of cells with established dengue virus type 2 infection induces cell death that is accompanied by a reduced ability of TNF-α to activate nuclear factor κB and reduced sphingosine kinase-1 activity. J Gen Virol92:807–818 [CrossRef][PubMed]
    [Google Scholar]
  56. Whitehorn J., Yacoub S., Anders K. L., Macareo L. R., Cassetti M. C., Nguyen Van V. C., Shi P. Y., Wills B., Simmons C. P.. 2014; Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions. PLoS Negl Trop Dis8:e3025 [CrossRef][PubMed]
    [Google Scholar]
  57. WHO 2009; Dengue. Guidelines for Diagnosis, Treatment, Prevention and Control Geneva: World Health Organization;
    [Google Scholar]
  58. Xia P., Wadham C.. 2011; Sphingosine 1-phosphate, a key mediator of the cytokine network: juxtacrine signaling. Cytokine Growth Factor Rev22:45–53 [CrossRef][PubMed]
    [Google Scholar]
  59. Xia P., Wang L., Moretti P. A., Albanese N., Chai F., Pitson S. M., D'Andrea R. J., Gamble J. R., Vadas M. A.. 2002; Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling. J Biol Chem277:7996–8003 [CrossRef][PubMed]
    [Google Scholar]
  60. Yamane D., Zahoor M. A., Mohamed Y. M., Azab W., Kato K., Tohya Y., Akashi H.. 2009; Inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis. J Biol Chem284:13648–13659 [CrossRef][PubMed]
    [Google Scholar]
  61. Yamane D., McGivern D. R., Wauthier E., Yi M., Madden V. J., Welsch C., Antes I., Wen Y., Chugh P. E., other authors. 2014; Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med20:927–935 [CrossRef][PubMed]
    [Google Scholar]
  62. Yang C. H., Murti A., Pfeffer S. R., Fan M., Du Z., Pfeffer L. M.. 2008; The role of TRAF2 binding to the type I interferon receptor in alternative NFκB activation and antiviral response. J Biol Chem283:14309–14316 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000334
Loading
/content/journal/jgv/10.1099/jgv.0.000334
Loading

Data & Media loading...

Supplements

Supplementary Data

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error