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Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm

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Abstract

Initial and early tissue injury associated with severe influenza virus infection is the result of both virus-mediated lysis of infected pulmonary cells coupled with an exuberant immune response generated against the virus. The excessive host immune response associated with influenza virus infection has been termed “cytokine storm.” Therapies that target virus replication are available; however, the selective pressure by such antiviral drugs on the virus often results in mutation and the escape of virus progeny now resistant to the antiviral regimen, thereby rendering such treatments ineffective. This event highlights the necessity for developing novel methods to combat morbidity and mortality caused by influenza virus infection. One potential method is restricting the host’s immune response. However, prior treatment regimens employing drugs like corticosteroids that globally suppress the host’s immune response were found unsatisfactory in large part because they disrupted the host’s ability to control virus replication. Here, we discuss a novel therapy that utilizes sphingosine-1-phosphate (S1P) receptor signaling that has the ability to significantly limit immunopathologic injury caused by the host’s innate and adaptive immune response, thereby significantly aborting morbidity and mortality associated with influenza virus infection. Moreover, S1P analog therapy allows for sufficient anti-influenza T cell and antibody formation to control infection. We review the anti-inflammatory effects of S1P signaling pathways and how modulation of these pathways during influenza virus infection restricts immunopathology. Finally, we discuss that combinatorial administration of S1P simultaneously with a current antiviral enhances the treatment efficacy for virulent influenza virus infections above that of either drug treatment alone. Interestingly, the scope of S1P receptor therapy reported here is likely to extend beyond influenza virus infection and could prove useful for the treatment of multiple maladies like other viral infections and autoimmune diseases where the host’s inflammatory response is a major component in the disease process.

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References

  1. Nicholson KG, Wood JM, Zambon M. Influenza. Lancet. 2003;362:1733–45.

    Article  PubMed  CAS  Google Scholar 

  2. Raymond FL, Caton AJ, Cox NJ, Kendal AP, Brownlee GG. The antigenicity and evolution of influenza H1 haemagglutinin, from 1950–1957 and 1977–1983: two pathways from one gene. Virology. 1986;148:275–87.

    Article  PubMed  CAS  Google Scholar 

  3. Webster RG, Laver WG, Air GM, Schild GC. Molecular mechanisms of variation in influenza viruses. Nature. 1982;296:115–21.

    Article  PubMed  CAS  Google Scholar 

  4. Seibert CW, Kaminski M, Philipp J, Rubbenstroth D, Albrecht RA, Schwalm F, Stertz S, Medina RA, Kochs G, Garcia-Sastre A, Staeheli P, Palese P. Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models. J Virol. 2010;84:11219–26.

    Article  PubMed  CAS  Google Scholar 

  5. Bloom JD, Gong LI, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 2010;328:1272–5.

    Article  PubMed  CAS  Google Scholar 

  6. Gerhard W, Mozdzanowska K, Zharikova D. Prospects for universal influenza virus vaccine. Emerg Infect Dis. 2006;12:569–74.

    PubMed  Google Scholar 

  7. Tscherne DM, Garcia-Sastre A. Virulence determinants of pandemic influenza viruses. J Clin Invest. 2011;121:6–13.

    Article  PubMed  CAS  Google Scholar 

  8. Garcia-Sastre A. Influenza virus receptor specificity: disease and transmission. Am J Pathol. 2010;176:1584–5.

    Article  PubMed  Google Scholar 

  9. Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, Hatta Y, Kim JH, Halfmann P, Hatta M, Feldmann F, Alimonti JB, Fernando L, Li Y, Katze MG, Feldmann H, Kawaoka Y. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445:319–23.

    Article  PubMed  CAS  Google Scholar 

  10. Cilloniz C, Shinya K, Peng X, Korth MJ, Proll SC, Aicher LD, Carter VS, Chang JH, Kobasa D, Feldmann F, Strong JE, Feldmann H, Kawaoka Y, Katze MG. Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog. 2009;5:e1000604.

    Article  PubMed  Google Scholar 

  11. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12:1203–7.

    Article  PubMed  Google Scholar 

  12. Openshaw PJ, Dunning J. Influenza vaccination: lessons learned from the pandemic (H1N1) 2009 influenza outbreak. Mucosal Immunol. 2010;3:422–4.

    Article  PubMed  CAS  Google Scholar 

  13. Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci. 2005;118:4605–12.

    Article  PubMed  CAS  Google Scholar 

  14. Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005;23:127–59.

    Article  PubMed  CAS  Google Scholar 

  15. Im DS. Pharmacological tools for lysophospholipid GPCRs: development of agonists and antagonists for LPA and S1P receptors. Acta Pharmacol Sin. 2010;31:1213–22.

    Article  PubMed  CAS  Google Scholar 

  16. Rivera J, Proia RL, Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008;8:753–63.

    Article  PubMed  CAS  Google Scholar 

  17. Rosen H, Gonzalez-Cabrera P, Marsolais D, Cahalan S, Don AS, Sanna MG. Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev. 2008;223:221–35.

    Article  PubMed  CAS  Google Scholar 

  18. Marsolais D, Rosen H. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov. 2009;8:297–307.

    Article  PubMed  CAS  Google Scholar 

  19. Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J, Derian CK, Andrade-Gordon P, Rosen H, Ruf W. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature. 2008;452:654–8.

    Article  PubMed  CAS  Google Scholar 

  20. Marsolais D, Hahm B, Walsh KB, Edelmann KH, McGavern D, Hatta Y, Kawaoka Y, Rosen H, Oldstone MB. A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc Natl Acad Sci USA. 2009;106:1560–5.

    Article  PubMed  CAS  Google Scholar 

  21. Shea BS, Brooks SF, Fontaine BA, Chun J, Luster AD, Tager AM. Prolonged S1P1 agonist exposure exacerbates vascular leak, fibrosis, and mortality after lung injury. Am J Respir Cell Mol Biol. 2010;43:662–73.

    Article  PubMed  CAS  Google Scholar 

  22. Rosen H, Liao J. Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm. Curr Opin Chem Biol. 2003;7:461–8.

    Article  PubMed  CAS  Google Scholar 

  23. Cahalan SM, Gonzalez-Cabrera PJ, Sarkisyan G, Nguyen N, Schaeffer MT, Huang L, Yeager A, Clemons B, Scott F, Rosen H. Actions of a picomolar short-acting S1P agonist in S1P-eGFP knock-in mice. Nat Chem Biol. 2011;7:254–6.

    Article  PubMed  CAS  Google Scholar 

  24. Kuiken T, Rimmelzwaan GF, Van Amerongen G, Osterhaus AD. Pathology of human influenza A (H5N1) virus infection in cynomolgus macaques (Macaca fascicularis). Vet Pathol. 2003;40:304–10.

    Article  PubMed  CAS  Google Scholar 

  25. Tumpey TM, Garcia-Sastre A, Taubenberger JK, Palese P, Swayne DE, Pantin-Jackwood MJ, Schultz-Cherry S, Solorzano A, Van Rooijen N, Katz JM, Basler CF. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol. 2005;79:14933–44.

    Article  PubMed  CAS  Google Scholar 

  26. Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 2008;4:e1000115.

    Article  PubMed  Google Scholar 

  27. Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol. 2008;3:499–522.

    Article  PubMed  CAS  Google Scholar 

  28. Kuiken T, Taubenberger JK. Pathology of human influenza revisited. Vaccine. 2008;26 Suppl 4:D59–66.

    Article  PubMed  Google Scholar 

  29. Peper RL, Van Campen H. Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia. Microb Pathog. 1995;19:175–83.

    Article  PubMed  CAS  Google Scholar 

  30. Hussell T, Pennycook A, Openshaw PJ. Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur J Immunol. 2001;31:2566–73.

    Article  PubMed  CAS  Google Scholar 

  31. Schmitz N, Kurrer M, Bachmann MF, Kopf M. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol. 2005;79:6441–8.

    Article  PubMed  CAS  Google Scholar 

  32. Oda T, Akaike T, Hamamoto T, Suzuki F, Hirano T, Maeda H. Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD. Science. 1989;244:974–6.

    Article  PubMed  CAS  Google Scholar 

  33. Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol. 2000;156:1951–9.

    Article  PubMed  CAS  Google Scholar 

  34. Sakai S, Kawamata H, Mantani N, Kogure T, Shimada Y, Terasawa K, Sakai T, Imanishi N, Ochiai H. Therapeutic effect of anti-macrophage inflammatory protein 2 antibody on influenza virus-induced pneumonia in mice. J Virol. 2000;74:2472–6.

    Article  PubMed  CAS  Google Scholar 

  35. Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180:2562–72.

    PubMed  CAS  Google Scholar 

  36. Walsh KB, Teijaro JR, Wilker PR, Jatzek A, Fremgen DM, Das SC, Watanabe T, Hatta M, Shinya K, Suresh M, Kawaoka Y, Rosen H, Oldstone MB. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci USA. 2011;108:12018–23.

    Article  PubMed  CAS  Google Scholar 

  37. Marsolais D, Hahm B, Edelmann KH, Walsh KB, Guerrero M, Hatta Y, Kawaoka Y, Roberts E, Oldstone MB, Rosen H. Local not systemic modulation of dendritic cell S1P receptors in lung blunts virus-specific immune responses to influenza. Mol Pharmacol. 2008;74:896–903.

    Article  PubMed  CAS  Google Scholar 

  38. Shimomura E, Suzuki F, Ishida N. Characterization of cells infiltrating the lungs of x-irradiated and nude mice after influenza virus infection. Microbiol Immunol. 1982;26:129–38.

    PubMed  CAS  Google Scholar 

  39. Wells MA, Albrecht P, Ennis FA. Recovery from a viral respiratory infection. I. Influenza pneumonia in normal and T-deficient mice. J Immunol. 1981;126:1036–41.

    PubMed  CAS  Google Scholar 

  40. Xu L, Yoon H, Zhao MQ, Liu J, Ramana CV, Enelow RI. Cutting edge: pulmonary immunopathology mediated by antigen-specific expression of TNF-alpha by antiviral CD8+ T cells. J Immunol. 2004;173:721–5.

    PubMed  CAS  Google Scholar 

  41. Sullivan JL, Mayner RE, Barry DW, Ennis FA. Influenza virus infection in nude mice. J Infect Dis. 1976;133:91–4.

    Article  PubMed  CAS  Google Scholar 

  42. Mumcuoglu M, Zakay-Rones Z, Weiss L, Slavin S. The effect of total or partial T lymphocyte depletion on susceptibility to influenza virus infection and development of antiviral immunity in lethally irradiated mice reconstituted with immune syngeneic bone marrow grafts. Bone Marrow Transplant. 1991;7:217–20.

    PubMed  CAS  Google Scholar 

  43. Doherty PC, Topham DJ, Tripp RA, Cardin RD, Brooks JW, Stevenson PG. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev. 1997;159:105–17.

    Article  PubMed  CAS  Google Scholar 

  44. Wang W, Graeler MH, Goetzl EJ. Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. FASEB J. 2005;19:1731–3.

    Article  PubMed  CAS  Google Scholar 

  45. Graeler M, Goetzl EJ. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 2002;16:1874–8.

    Article  PubMed  CAS  Google Scholar 

  46. Jin Y, Knudsen E, Wang L, Bryceson Y, Damaj B, Gessani S, Maghazachi AA. Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood. 2003;101:4909–15.

    Article  PubMed  CAS  Google Scholar 

  47. Wang W, Huang MC, Goetzl EJ. Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J Immunol. 2007;178:4885–90.

    PubMed  CAS  Google Scholar 

  48. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355–60.

    Article  PubMed  CAS  Google Scholar 

  49. Goetzl EJ, Liao JJ, Huang MC. Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity. Biochim Biophys Acta. 2008;1781:503–7.

    PubMed  CAS  Google Scholar 

  50. Pircher H, Burki K, Lang R, Hengartner H, Zinkernagel RM. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989;342:559–61.

    Article  PubMed  CAS  Google Scholar 

  51. McGill J, Heusel JW, Legge KL. Innate immune control and regulation of influenza virus infections. J Leukoc Biol. 2009;86:803–12.

    Article  PubMed  CAS  Google Scholar 

  52. GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, Thielemans K, Bennett C, Clausen BE, Hoogsteden HC, Osterhaus AD, Rimmelzwaan GF, Lambrecht BN. Clearance of influenza virus from the lung depends on migratory langerin + CD11b—but not plasmacytoid dendritic cells. J Exp Med. 2008;205:1621–34.

    Article  PubMed  CAS  Google Scholar 

  53. Kim TS, Braciale TJ. Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLoS One. 2009;4:e4204.

    Article  PubMed  Google Scholar 

  54. Oz-Arslan D, Ruscher W, Myrtek D, Ziemer M, Jin Y, Damaj BB, Sorichter S, Idzko M, Norgauer J, Maghazachi AA. IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids. J Leukoc Biol. 2006;80:287–97.

    Article  PubMed  CAS  Google Scholar 

  55. Idzko M, Hammad H, van Nimwegen M, Kool M, Muller T, Soullie T, Willart MA, Hijdra D, Hoogsteden HC, Lambrecht BN. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest. 2006;116:2935–44.

    Article  PubMed  CAS  Google Scholar 

  56. Czeloth N, Bernhardt G, Hofmann F, Genth H, Forster R. Sphingosine-1-phosphate mediates migration of mature dendritic cells. J Immunol. 2005;175:2960–7.

    PubMed  CAS  Google Scholar 

  57. Czeloth N, Schippers A, Wagner N, Muller W, Kuster B, Bernhardt G, Forster R. Sphingosine-1 phosphate signaling regulates positioning of dendritic cells within the spleen. J Immunol. 2007;179:5855–63.

    PubMed  CAS  Google Scholar 

  58. Lan YY, De Creus A, Colvin BL, Abe M, Brinkmann V, Coates PT, Thomson AW. The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am J Transplant. 2005;5:2649–59.

    Article  PubMed  CAS  Google Scholar 

  59. Lamana A, Martin P, de la Fuente H, Martinez-Munoz L, Cruz-Adalia A, Ramirez-Huesca M, Escribano C, Gollmer K, Mellado M, Stein JV, Rodriguez-Fernandez JL, Sanchez-Madrid F, Del Hoyo GM. CD69 modulates sphingosine-1-phosphate-induced migration of skin dendritic cells. J Invest Dermatol. 2011;131:1503–12.

    Article  PubMed  CAS  Google Scholar 

  60. Rathinasamy A, Czeloth N, Pabst O, Forster R, Bernhardt G. The origin and maturity of dendritic cells determine the pattern of sphingosine 1-phosphate receptors expressed and required for efficient migration. J Immunol. 2010;185:4072–81.

    Article  PubMed  CAS  Google Scholar 

  61. Lan YY, Tokita D, Wang Z, Wang HC, Zhan J, Brinkmann V, Thomson AW. Sphingosine 1-phosphate receptor agonism impairs skin dendritic cell migration and homing to secondary lymphoid tissue: association with prolonged allograft survival. Transpl Immunol. 2008;20:88–94.

    Article  PubMed  CAS  Google Scholar 

  62. Heng Y, Ma Y, Yin H, Duan L, Xiong P, Xu Y, Feng W, Fang M, Tan Z, Chen Y, Zheng F, Gong F. Adoptive transfer of FTY720-treated immature BMDCs significantly prolonged cardiac allograft survival. Transpl Int. 2010;23:1259–70.

    Article  PubMed  CAS  Google Scholar 

  63. Muller H, Hofer S, Kaneider N, Neuwirt H, Mosheimer B, Mayer G, Konwalinka G, Heufler C, Tiefenthaler M. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol. 2005;35:533–45.

    Article  PubMed  Google Scholar 

  64. Zheng BJ, Chan KW, Lin YP, Zhao GY, Chan C, Zhang HJ, Chen HL, Wong SS, Lau SK, Woo PC, Chan KH, Jin DY, Yuen KY. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci USA. 2008;105:8091–6.

    Article  PubMed  CAS  Google Scholar 

  65. Falagas ME, Vouloumanou EK, Baskouta E, Rafailidis PI, Polyzos K, Rello J. Treatment options for 2009 H1N1 influenza: evaluation of the published evidence. Int J Antimicrob Agents. 2010;35:421–30.

    Article  PubMed  CAS  Google Scholar 

  66. Carter MJ. A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza. J Med Microbiol. 2007;56:875–83.

    Article  PubMed  CAS  Google Scholar 

  67. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci USA. 2007;104:12479–81.

    Article  PubMed  Google Scholar 

  68. Takuwa N, Ohkura S, Takashima S, Ohtani K, Okamoto Y, Tanaka T, Hirano K, Usui S, Wang F, Du W, Yoshioka K, Banno Y, Sasaki M, Ichi I, Okamura M, Sugimoto N, Mizugishi K, Nakanuma Y, Ishii I, Takamura M, Kaneko S, Kojo S, Satouchi K, Mitumori K, Chun J, Takuwa Y. S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovasc Res. 2010;85:484–93.

    Article  PubMed  CAS  Google Scholar 

  69. Murakami A, Takasugi H, Ohnuma S, Koide Y, Sakurai A, Takeda S, Hasegawa T, Sasamori J, Konno T, Hayashi K, Watanabe Y, Mori K, Sato Y, Takahashi A, Mochizuki N, Takakura N. Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist. Mol Pharmacol. 2010;77:704–13.

    Article  PubMed  CAS  Google Scholar 

  70. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This is Publication Number 21388 from the Department of Immunology and Microbial Science, the Department of Chemical Physiology, and The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute (TSRI). This work was supported in part by USPHS grants AI074564 (MBAO, HR, KW, JT), AI009484 (MBAO), AI005509 (HR), MH084512 (HR) and NIH training grants NS041219 (KW), AI007244 (KW), AI007364 (JT) and American Heart Association Fellowship 11POST7430106 (JT). We thank Daniel Fremgen for excellent technical assistance.

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  1. Department of Immunology and Microbial Science, The Scripps Research Institute, IMM-6, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA

    Kevin B. Walsh, John R. Teijaro & Michael B. A. Oldstone

  2. Department of Chemical Physiology, The Scripps Research Institute, MEM-L55, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA

    Hugh Rosen

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  1. Kevin B. Walsh
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  2. John R. Teijaro
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Correspondence to Hugh Rosen or Michael B. A. Oldstone.

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Kevin B. Walsh, John R. Teijaro contributed equally.

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Walsh, K.B., Teijaro, J.R., Rosen, H. et al. Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm. Immunol Res 51, 15–25 (2011). https://doi.org/10.1007/s12026-011-8240-z

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