Viruses attempt to create a distinctive cellular environment to favor viral replication and spread. Recent studies uncovered new functions of the sphingolipid signaling/metabolism during pathogenic virus infections. While sphingolipids such as sphingomyelin and ceramide were reported to influence the entry step of several viruses, sphingolipid-metabolizing enzymes could directly alter viral replication processes. Influenza virus was shown to increase the level of sphingosine kinase (SK) 1 to promote virus propagation. The mechanism involves regulation of intracellular signaling pathways, leading to the amplification of influenza viral RNA synthesis and nuclear export of viral ribonucleoprotein (RNP) complex. However, bovine viral diarrhea virus inhibits SK1 to enhance the efficacy of virus replication, demonstrating the presence of virus-specific strategies for modulation of the sphingolipid system. Therefore, investigating the sphingolipid metabolism and signaling in the context of virus replication could help us design innovative therapeutic approaches to improve human health. 1. Introduction Over the last twenty years, the field of sphingolipid system has received enormous attention of scientists and clinicians, since the sphingolipids have numerous important biological functions and are therapeutically applicable to the treatment of human diseases [1–5]. The sphingolipids are bioactive mediators and include sphingomyelin, ceramide, ceramide-1-phosphate, sphingosine, and sphingosine 1-phosphate (S1P) (Figure 1(a)). The levels of these sphingolipids are tightly regulated by cellular metabolizing enzymes to maintain normal cellular physiological conditions [6, 7]. The sphingosine analog FTY720 (fingolimod, gilenya) (Figure 1(b)) transiently represses the exit of T lymphocytes from lymph nodes and acts as an agonist of S1P receptors (S1P1 and S1P3–5) except for S1P receptor 2 [8, 9]. FTY720, which is a derivative of myriocin that is found in a fungus and used in Chinese medicine, is the first oral therapeutic agent approved by the US FDA to treat multiple sclerosis (MS) [10, 11]. Also, the FTY720 derivative AAL-R or S1P receptor 1 agonist was shown to alleviate influenza virus-induced immunopathology [12–15] and the detailed information about this is found in excellent review articles written by Oldstone and Rosen’s groups [16–18]. Figure 1: The sphingolipid system. (a) The pathway of sphingolipid synthesis and degradation by catalytic enzymes. (b) Shown are chemical structures of the sphingolipids (ceramide, sphingosine, and S1P) and the sphingosine
References
[1]
Y. Edmonds, S. Milstien, and S. Spiegel, “Development of small-molecule inhibitors of sphingosine-1-phosphate signaling,” Pharmacology and Therapeutics, vol. 132, no. 3, pp. 352–360, 2011.
[2]
M. Maceyka, K. B. Harikumar, S. Milstien, and S. Spiegel, “Sphingosine-1-phosphate signaling and its role in disease,” Trends in Cell Biology, vol. 22, no. 1, pp. 50–60, 2012.
[3]
K. A. Orr Gandy and L. M. Obeid, “Targeting the sphingosine kinase/sphingosine 1-phosphate pathway in disease: review of sphingosine kinase inhibitors,” Biochimica Et Biophysica Acta, vol. 1831, pp. 157–166, 2013.
[4]
B. Oskouian and J. D. Saba, “Cancer treatment strategies targeting sphingolipid metabolism,” Advances in Experimental Medicine and Biology, vol. 688, pp. 185–205, 2010.
[5]
C. E. Stevenson, K. Takabe, M. Nagahashi, S. Milstien, and S. Spiegel, “Targeting sphingosine-1-phosphate in hematologic malignancies,” Anti-Cancer Agents in Medicinal Chemistry, vol. 11, no. 9, pp. 794–798, 2011.
[6]
H. Le Stunff, S. Milstien, and S. Spiegel, “Generation and metabolism of bioactive sphingosine-1-phosphate,” Journal of Cellular Biochemistry, vol. 92, no. 5, pp. 882–899, 2004.
[7]
S. M. Pitson, “Regulation of sphingosine kinase and sphingolipid signaling,” Trends in Biochemical Sciences, vol. 36, no. 2, pp. 97–107, 2011.
[8]
V. Brinkmann, M. D. Davis, C. E. Heise et al., “The immune modulator FTY720 targets sphingosine 1-phosphate receptors,” Journal of Biological Chemistry, vol. 277, no. 24, pp. 21453–21457, 2002.
[9]
S. Mandala, R. Hajdu, J. Bergstrom et al., “Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists,” Science, vol. 296, no. 5566, pp. 346–349, 2002.
[10]
V. Brinkmann, A. Billich, T. Baumruker et al., “Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis,” Nature Reviews Drug Discovery, vol. 9, no. 11, pp. 883–897, 2010.
[11]
A. Horga and X. Montalban, “FTY720 (fingolimod) for relapsing multiple sclerosis,” Expert Review of Neurotherapeutics, vol. 8, no. 5, pp. 699–714, 2008.
[12]
D. Marsolais, B. Hahm, K. H. Edelmann et al., “Local not systemic modulation of dendritic cell S1P receptors in lung blunts virus-specific immune responses to influenza,” Molecular Pharmacology, vol. 74, no. 3, pp. 896–903, 2008.
[13]
D. Marsolais, B. Hahm, K. B. Walsh et al., “A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 5, pp. 1560–1565, 2009.
[14]
J. R. Teijaro, K. B. Walsh, S. Cahalan et al., “Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection,” Cell, vol. 146, no. 6, pp. 980–991, 2011.
[15]
K. B. Walsh, J. R. Teijaro, P. R. Wilker et al., “Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 29, pp. 12018–12023, 2011.
[16]
M. B. Oldstone, J. R. Teijaro, K. B. Walsh, and H. Rosen, “Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection,” Virology, vol. 435, pp. 92–101, 2013.
[17]
H. Rosen, R. C. Stevens, M. Hanson, E. Roberts, and M. B. Oldstone, “Sphingosine-1-phosphate and its receptors: structure, signaling, and influence,” Annual Review of Biochemistry, vol. 82, pp. 637–662, 2013.
[18]
K. B. Walsh, J. R. Teijaro, H. Rosen, and M. B. A. Oldstone, “Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm,” Immunologic Research, vol. 51, no. 1, pp. 15–25, 2011.
[19]
S. W. Paugh, B. S. Paugh, M. Rahmani et al., “A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia,” Blood, vol. 112, no. 4, pp. 1382–1391, 2008.
[20]
Y.-J. Seo, S. Alexander, and B. Hahm, “Does cytokine signaling link sphingolipid metabolism to host defense and immunity against virus infections?” Cytokine and Growth Factor Reviews, vol. 22, no. 1, pp. 55–61, 2011.
[21]
Y.-J. Seo, C. Blake, S. Alexander, and B. Hahm, “Sphingosine 1-phosphate-metabolizing enzymes control influenza virus propagation and viral cytopathogenicity,” Journal of Virology, vol. 84, no. 16, pp. 8124–8131, 2010.
[22]
N. J. Machesky, G. Zhang, B. Raghavan et al., “Human cytomegalovirus regulates bioactive sphingolipids,” Journal of Biological Chemistry, vol. 283, no. 38, pp. 26148–26160, 2008.
[23]
M. M. Monick, K. Cameron, L. S. Powers et al., “Sphingosine kinase mediates activation of extracellular signal-related kinase and Akt by respiratory syncytial virus,” American Journal of Respiratory Cell and Molecular Biology, vol. 30, no. 6, pp. 844–852, 2004.
[24]
Y. J. Seo, C. J. Pritzl, M. Vijayan 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, vol. 8, no. 8, Article ID e75005, 2013.
[25]
S. Wati, S. M. Rawlinson, R. A. Ivanov et al., “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,” Journal of General Virology, vol. 92, no. 4, pp. 807–818, 2011.
[26]
D. Yamane, M. A. Zahoor, Y. M. Mohamed et al., “Inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis,” Journal of Biological Chemistry, vol. 284, no. 20, pp. 13648–13659, 2009.
[27]
P. Adams, “The influenza enigma,” Bulletin of the World Health Organization, vol. 90, pp. 250–251, 2012.
[28]
R. A. Medina and A. García-Sastre, “Influenza A viruses: new research developments,” Nature Reviews Microbiology, vol. 9, no. 8, pp. 590–603, 2011.
[29]
G. Neumann, G. G. Brownlee, E. Fodor, and Y. Kawaoka, “Orthomyxovirus replication, transcription, and polyadenylation,” Current Topics in Microbiology and Immunology, vol. 283, pp. 121–143, 2004.
[30]
MMWR, “Update: influenza activity—United States and worldwide,” Morbidity and Mortality Weekly Report, vol. 62, pp. 838–842, 2013.
[31]
M. Imai and Y. Kawaoka, “The role of receptor binding specificity in interspecies transmission of influenza viruses,” Current Opinion in Virology, vol. 2, no. 2, pp. 160–167, 2012.
[32]
T. T. Lam, J. Wang, Y. Shen et al., “The genesis and source of the H7N9 influenza viruses causing human infections in China,” Nature, vol. 502, pp. 241–244, 2013.
[33]
WHO, “Antigenic and genetic characteristics of influenza A(H5N1) and influenza A(H9N2) viruses for development of candidate vaccines viruses for pandemic preparedness,” The Weekly Epidemiological Record, vol. 86, pp. 93–100, 2011.
[34]
L. H. Pinto and R. A. Lamb, “The M2 proton channels of influenza A and B viruses,” Journal of Biological Chemistry, vol. 281, no. 14, pp. 8997–9000, 2006.
[35]
S. Boivin, S. Cusack, R. W. H. Ruigrok, and D. J. Hart, “Influenza A virus polymerase: structural insights into replication and host adaptation mechanisms,” Journal of Biological Chemistry, vol. 285, no. 37, pp. 28411–28417, 2010.
[36]
D. P. Nayak, R. A. Balogun, H. Yamada, Z. H. Zhou, and S. Barman, “Influenza virus morphogenesis and budding,” Virus Research, vol. 143, no. 2, pp. 147–161, 2009.
[37]
D. Elton, M. Simpson-Holley, K. Archer et al., “Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway,” Journal of Virology, vol. 75, no. 1, pp. 408–419, 2001.
[38]
A. C. Hurt, T. Chotpitayasunondh, N. J. Cox et al., “Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives,” The Lancet Infectious Diseases, vol. 12, no. 3, pp. 240–248, 2012.
[39]
WHO, “Global monitoring of antiviral resistance in currently circulating human influenza viruses,” Weekly Epidemiological Record, vol. 86, pp. 497–501, 2011.
[40]
S. Pleschka, T. Wolff, C. Ehrhardt et al., “Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade,” Nature Cell Biology, vol. 3, no. 3, pp. 301–305, 2001.
[41]
L. C. Platanias, “Mechanisms of type-I- and type-II-interferon-mediated signalling,” Nature Reviews Immunology, vol. 5, no. 5, pp. 375–386, 2005.
[42]
D. Pchejetski, J. Nunes, K. Coughlan et al., “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,” Immunology and Cell Biology, vol. 89, no. 2, pp. 268–274, 2011.
[43]
S. E. Alvarez, K. B. Harikumar, N. C. Hait et al., “Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2,” Nature, vol. 465, no. 7301, pp. 1084–1088, 2010.
[44]
P. Xia, L. Wang, P. A. B. Moretti et al., “Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling,” Journal of Biological Chemistry, vol. 277, no. 10, pp. 7996–8003, 2002.
[45]
F. G. Tafesse, S. Sanyal, J. Ashour et al., “Intact sphingomyelin biosynthetic pathway is essential for intracellular transport of influenza virus glycoproteins,” Proceedings of the National Academy of Sciences, vol. 110, pp. 6406–6411, 2013.
[46]
T. Shimizu, N. Takizawa, K. Watanabe, K. Nagata, and N. Kobayashi, “Crucial role of the influenza virus NS2 (NEP) C-terminal domain in M1 binding and nuclear export of vRNP,” FEBS Letters, vol. 585, no. 1, pp. 41–46, 2011.
[47]
M. E. Lindsay, J. M. Holaska, K. Welch, B. M. Paschal, and I. G. Macara, “Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export,” Journal of Cell Biology, vol. 153, no. 7, pp. 1391–1402, 2001.
[48]
R. Predicala and Y. Zhou, “The role of Ran-binding protein 3 during influenza A virus replication,” Journal of General Virology, vol. 94, pp. 977–984, 2013.
[49]
P. Michael, D. Brabant, F. Bleiblo et al., “Influenza A induced cellular signal transduction pathways,” Journal of Thoracic Disease, vol. 5, pp. S132–S141, 2013.
[50]
M. S. Hayden and S. Ghosh, “NF-κB in immunobiology,” Cell Research, vol. 21, no. 2, pp. 223–244, 2011.
[51]
M. S. Hayden and S. Ghosh, “NF-κB, the first quarter-century: remarkable progress and outstanding questions,” Genes and Development, vol. 26, no. 3, pp. 203–234, 2012.
[52]
G. Courtois and T. D. Gilmore, “Mutations in the NF-κB signaling pathway: implications for human disease,” Oncogene, vol. 25, no. 51, pp. 6831–6843, 2006.
[53]
J. Hiscott, H. Kwon, and P. Génin, “Hostile takeovers: viral appropriation of the NF-κB pathway,” Journal of Clinical Investigation, vol. 107, no. 2, pp. 143–151, 2001.
[54]
A. Oeckinghaus, M. S. Hayden, and S. Ghosh, “Crosstalk in NF-κB signaling pathways,” Nature Immunology, vol. 12, no. 8, pp. 695–708, 2011.
[55]
J. L. Pomerantz and D. Baltimore, “Two pathways to NF-κB,” Molecular Cell, vol. 10, no. 4, pp. 693–695, 2002.
[56]
Q. Li and I. M. Verma, “NF-kappaB regulation in the immune system,” Nature Reviews Immunology, vol. 2, pp. 725–734, 2002.
[57]
T. D. Gilmore, “Introduction to NF-κB: players, pathways, perspectives,” Oncogene, vol. 25, no. 51, pp. 6680–6684, 2006.
[58]
L. A. Solt and M. J. May, “The IκB kinase complex: master regulator of NF-κB signaling,” Immunologic Research, vol. 42, no. 1–3, pp. 3–18, 2008.
[59]
M. S. Hayden, A. P. West, and S. Ghosh, “NF-κB and the immune response,” Oncogene, vol. 25, no. 51, pp. 6758–6780, 2006.
[60]
X. Wang, M. Li, H. Zheng et al., “Influenza A virus NS1 protein prevents activation of NF-κB and induction of alpha/beta interferon,” Journal of Virology, vol. 74, no. 24, pp. 11566–11573, 2000.
[61]
M. Joo, Y. S. Hahn, M. Kwon, R. T. Sadikot, T. S. Blackwell, and J. W. Christman, “Hepatitis C virus core protein suppresses NF-κB activation and cyclooxygenase-2 expression by direct interaction with IκB kinase β,” Journal of Virology, vol. 79, no. 12, pp. 7648–7657, 2005.
[62]
S. Gao, L. Song, J. Li et al., “Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK,” Cellular Microbiology, vol. 14, pp. 1849–1866, 2012.
[63]
K. M. Schuhmann, C. K. Pfaller, and K.-K. Conzelmann, “The measles virus V protein binds to p65 (RelA) to suppress NF-κB activity,” Journal of Virology, vol. 85, no. 7, pp. 3162–3171, 2011.
[64]
H. Kwon, N. Pelletier, C. DeLuca et al., “Inducible expression of IκBα represser mutants interferes with NF-κB activity and HIV-1 replication in Jurkat T cells,” Journal of Biological Chemistry, vol. 273, no. 13, pp. 7431–7440, 1998.
[65]
A. Lavorgna and E. W. Harhaj, “EBV LMP1: new and shared pathways to NF-κB activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 7, pp. 2188–2189, 2012.
[66]
N. Kumar, Z.-T. Xin, Y. Liang, H. Ly, and Y. Liang, “NF-κB signaling differentially regulates influenza virus RNA synthesis,” Journal of Virology, vol. 82, no. 20, pp. 9880–9889, 2008.
[67]
F. Nimmerjahn, D. Dudziak, U. Dirmeier et al., “Active NF-κB signalling is a prerequisite for influenza virus infection,” Journal of General Virology, vol. 85, no. 8, pp. 2347–2356, 2004.
[68]
E.-K. Pauli, M. Schmolke, T. Wolff et al., “Influenza A virus inhibits type I IFN signaling via NF-κB-dependent induction of SOCS-3 expression,” PLoS Pathogens, vol. 4, no. 11, Article ID e1000196, 2008.
[69]
W. J. Wurzer, C. Ehrhardt, S. Pleschka et al., “NF-κB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation,” Journal of Biological Chemistry, vol. 279, no. 30, pp. 30931–30937, 2004.
[70]
S.-O. Yoon, S. Shin, Y. Liu et al., “Ran-binding protein 3 phosphorylation links the ras and PI3-kinase pathways to nucleocytoplasmic transport,” Molecular Cell, vol. 29, no. 3, pp. 362–375, 2008.
[71]
X. Shu, W. Wu, R. D. Mosteller, and D. Broek, “Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases,” Molecular and Cellular Biology, vol. 22, no. 22, pp. 7758–7768, 2002.
[72]
S. M. Pitson, P. A. B. Moretti, J. R. Zebol et al., “Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation,” EMBO Journal, vol. 22, no. 20, pp. 5491–5500, 2003.
[73]
J. Herz, J. Pardo, H. Kashkar et al., “Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes,” Nature Immunology, vol. 10, no. 7, pp. 761–768, 2009.
[74]
E. T. Samy, C. A. Meyer, P. Caplazi et al., “Cutting edge: modulation of intestinal autoimmunity and IL-2 signaling by sphingosine kinase 2 independent of sphingosine 1-phosphate,” Journal of Immunology, vol. 179, no. 9, pp. 5644–5648, 2007.
[75]
Y. J. Seo, C. J. Pritzl, M. Vijayan, C. R. Blake, M. E. McClain, and B. Hahm, “Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways,” Journal of Immunology, vol. 188, pp. 4759–4768, 2012.
[76]
J. H. Xie, N. Nomura, S. L. Koprak, E. J. Quackenbush, M. J. Forrest, and H. Rosen, “Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells,” Journal of Immunology, vol. 170, no. 7, pp. 3662–3670, 2003.
