Innate Immune Responses to West Nile Virus Infection

  • Alvaro Arjona
  • Erol Fikrig
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


Innate antiviral immunity is activated by the detection of conserved virus-associated molecular motifs by host-encoded pathogen-recognition receptors (PRRs). This phenomenon triggers the production of antiviral and proinflammatory cytokines as well as the expression of costimulatory molecules in immune cells, leading to the establishment of an antiviral state and the induction of adaptive immune responses. In this chapter we review our current understanding of the innate immune mechanisms that mediate the recognition of West Nile virus (WNV) infection. The role of innate immune cells and cytokines in WNV immunopathogenesis is also discussed. Paradoxically, although many of the innate responses induced by WNV infection are protective, others favor WNV neuroinvasion by their detrimental effect on blood–brain barrier permeability.


West Nile Virus Migration Inhibitory Factor Innate Response West Nile Virus Infection Migration Inhibitory Factor Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abbott NJ. (2000) Inflammatory mediators and modulation of blood–brain barrier permeability. Cell Mol Neurobiol 20:131–147CrossRefPubMedGoogle Scholar
  2. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738CrossRefPubMedGoogle Scholar
  3. Andoniou CE, Andrews DM, Degli-Esposti MA. (2006) Natural killer cells in viral infection: more than just killers. Immunol Rev 214:239–250CrossRefPubMedGoogle Scholar
  4. Arjona A et al. (2007) Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 117:3059–3066CrossRefPubMedGoogle Scholar
  5. Arndt U et al. (2002) Release of macrophage migration inhibitory factor and CXCL8/inter-leukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection. J Virol 76:9298–9306CrossRefPubMedGoogle Scholar
  6. Bacher M, Eickmann M, Schrader J, Gemsa D, Heiske A. (2002) Human cytomegalovirus-mediated induction of MIF in fibroblasts. Virology 299:32–37CrossRefPubMedGoogle Scholar
  7. Baugh JA et al. (2002) A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3:170–176CrossRefPubMedGoogle Scholar
  8. Bell JK, Askins J, Hall PR, Davies DR, Segal DM. (2006a) The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci USA 103:8792–8797CrossRefGoogle Scholar
  9. Bell JK et al. (2006b) The molecular structure of the TLR3 extracellular domain. J Endotoxin Res 12:375–378CrossRefGoogle Scholar
  10. Ben-Nathan D, Huitinga I, Lustig S, van Rooijen N, Kobiler D. (1996) West Nile virus neu-roinvasion and encephalitis induced by macrophage depletion in mice. Arch Virol 141:459–469CrossRefPubMedGoogle Scholar
  11. Boehme KW, Singh J, Perry ST, Compton T. (2004) Human cytomegalovirus elicits a coordinated cellular antiviral response via envelope glycoprotein B. J Virol 78:1202–1211CrossRefPubMedGoogle Scholar
  12. Byrne SN, Halliday GM, Johnston LJ, King NJ. (2001) Interleukin-1beta but not tumor necrosis factor is involved in West Nile virus-induced Langerhans cell migration from the skin in C57BL/6 mice. J Invest Dermatol 117:702–709CrossRefPubMedGoogle Scholar
  13. Calandra T, Roger T. (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3:791–800CrossRefPubMedGoogle Scholar
  14. Calandra T et al. (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164–170CrossRefPubMedGoogle Scholar
  15. Caparros E et al. (2006) DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production. Blood 107:3950–3958CrossRefPubMedGoogle Scholar
  16. Carding SR, Egan PJ. (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2:336–345CrossRefPubMedGoogle Scholar
  17. Cheeran MC, Hu S, Sheng WS, Rashid A, Peterson PK, Lokensgard JR. (2005) Differential responses of human brain cells to West Nile virus infection. J Neurovirol 11:512–524CrossRefPubMedGoogle Scholar
  18. Chen LC et al. (2006) Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg 74:142–147PubMedGoogle Scholar
  19. Cheng Y, King NJ, Kesson AM. (2004) Major histocompatibility complex class I (MHC-I) induction by West Nile virus: involvement of 2 signaling pathways in MHC-I up-regulation. J Infect Dis 189:658–668CrossRefPubMedGoogle Scholar
  20. Choe J, Kelker MS, Wilson IA. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585CrossRefPubMedGoogle Scholar
  21. Cvetkovic I et al. (2005) Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes. Endocrinology 146:2942–2951CrossRefPubMedGoogle Scholar
  22. Daffis S, Samuel MA, Keller BC, Gale M Jr, Diamond MS. (2007) Cell-specific IRF-3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms. PLoS Pathog 3:e106CrossRefPubMedGoogle Scholar
  23. David JR. (1966) Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci USA 56:72–77CrossRefPubMedGoogle Scholar
  24. Davis CW, Mattei LM, Nguyen HY, Ansarah-Sobrinho C, Doms RW, Pierson TC. (2006a) The location of asparagine-linked glycans on West Nile virions controls their interactions with CD209 (dendritic cell-specific ICAM-3 grabbing nonintegrin). J Biol Chem 281:37183–37194CrossRefGoogle Scholar
  25. Davis CW, Nguyen HY, Hanna SL, Sanchez MD, Doms RW, Pierson TC. (2006b) West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol 80:1290–1301CrossRefGoogle Scholar
  26. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303 : 1529–1531CrossRefPubMedGoogle Scholar
  27. Fredericksen BL, Gale M, Jr. (2006) West Nile virus evades activation of interferon regulatory factor 3 through RIG-I-dependent and -independent pathways without antagonizing host defense signaling. J Virol 80:2913–2923CrossRefPubMedGoogle Scholar
  28. Garcia-Tapia D, Loiacono CM, Kleiboeker SB. (2006) Replication of West Nile virus in equine peripheral blood mononuclear cells. Vet Immunol Immunopathol 110:229–244CrossRefPubMedGoogle Scholar
  29. Geijtenbeek TB et al. (2003) Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197:7–17CrossRefPubMedGoogle Scholar
  30. Getts DR et al. (2007) Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures. J Neurochem 103:1019–1030CrossRefPubMedGoogle Scholar
  31. Gilfoy FD, Mason PW. (2007) West Nile virus-induced interferon production is mediated by the double-stranded RNA-dependent protein kinase PKR. J Virol 81:11148–11158CrossRefPubMedGoogle Scholar
  32. Gitlin L et al.(2006) Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyr ibocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA 103:8459–8464CrossRefPubMedGoogle Scholar
  33. Hayday AC. (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026CrossRefPubMedGoogle Scholar
  34. Herzer K et al. (2003) Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity. J Virol 77:8299–8309CrossRefPubMedGoogle Scholar
  35. Iwasaki A, Medzhitov R. (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995CrossRefPubMedGoogle Scholar
  36. Jin MS et al. (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082CrossRefPubMedGoogle Scholar
  37. Johnston LJ, Halliday GM, King NJ. (1996) Phenotypic changes in Langerhans' cells after infection with arboviruses: a role in the immune response to epidermally acquired viral infection? J Virol 70:4761–4766PubMedGoogle Scholar
  38. Johnston LJ, Halliday GM, King NJ. (2000) Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus. J Invest Dermatol 114:560–568CrossRefPubMedGoogle Scholar
  39. Kato H et al. (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105CrossRefPubMedGoogle Scholar
  40. Kawai T, Akira S. (2006) Innate immune recognition of viral infection. Nat Immunol 7:131–137CrossRefPubMedGoogle Scholar
  41. Kelley TW, Prayson RA, Ruiz AI, Isada CM, Gordon SM. (2003) The neuropathology of West Nile virus meningoencephalitis. A report of two cases and review of the literature. Am J Clin Pathol 119:749–753CrossRefPubMedGoogle Scholar
  42. Kim HM et-al.(2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–917CrossRefPubMedGoogle Scholar
  43. King NJ, Kesson AM. (2003) Interaction of flaviviruses with cells of the vertebrate host and decoy of the immune response. Immunol Cell Biol 81:207–216CrossRefPubMedGoogle Scholar
  44. King NJ, Maxwell LE, Kesson AM. (1989) Induction of class I major histocompatibility complex antigen expression by West Nile virus on gamma interferon-refractory early murine trophoblast cells. Proc Natl Acad Sci USA 86:911–915CrossRefPubMedGoogle Scholar
  45. Kobayashi KS, Flavell RA. (2004) Shielding the double-edged sword: negative regulation of the innate immune system. J Leukoc Biol 75:428–433CrossRefPubMedGoogle Scholar
  46. Kreil TR, Eibl MM. (1996) Nitric oxide and viral infection: NO antiviral activity against a flavivirus in vitro, and evidence for contribution to pathogenesis in experimental infection in vivo. Virology 219:304–306CrossRefPubMedGoogle Scholar
  47. Kulkarni AB, Mullbacher A, Blanden RV. (1991) Functional analysis of macrophages, B cells and splenic dendritic cells as antigen-presenting cells in West Nile virus-specific murine T lymphocyte proliferation. Immunol Cell Biol 69 (Pt 2):71–80CrossRefPubMedGoogle Scholar
  48. Kurt-Jones EA et al. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398–401CrossRefGoogle Scholar
  49. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMedGoogle Scholar
  50. Leng L, Bucala R. (2005) Macrophage migration inhibitory factor. Crit Care Med 33:S475–477CrossRefPubMedGoogle Scholar
  51. Lin YL et al. (1997) Inhibition of Japanese encephalitis virus infection by nitric oxide: antiviral effect of nitric oxide on RNA virus replication. J Virol 71:5227–5235PubMedGoogle Scholar
  52. Liu Y, King N, Kesson A, Blanden RV, Mullbacher A. (1988) West Nile virus infection modulates the expression of class I and class II MHC antigens on astrocytes in vitro. Ann N Y Acad Sci 540:483–485CrossRefPubMedGoogle Scholar
  53. Liu Y, King N, Kesson A, Blanden RV, Mullbacher A. (1989) Flavivirus infection up-regulates the expression of class I and class II major histocompatibility antigens on and enhances T cell recognition of astrocytes in vitro. J Neuroimmunol 21:157–168CrossRefPubMedGoogle Scholar
  54. Lubetsky JB et al. (2002) The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem 277:24976–24982CrossRefPubMedGoogle Scholar
  55. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. (2003) Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198:513–520CrossRefPubMedGoogle Scholar
  56. Lund JM et-al.(2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603CrossRefPubMedGoogle Scholar
  57. van Marle G et-al.(2007) West nile virus-induced neuroinflammation: glial infection and cap-sid protein-mediated neurovirulence. J Virol 81:10933–10949CrossRefPubMedGoogle Scholar
  58. Mizue Y et al. (2005) Role for macrophage migration inhibitory factor in asthma. Proc Natl Acad Sci USA 102:14410–14415CrossRefPubMedGoogle Scholar
  59. Morrissette N, Gold E, Aderem A. (1999) The macrophage–a cell for all seasons. Trends Cell Biol 9:199–201CrossRefPubMedGoogle Scholar
  60. Nohara H et al. (2004) Association of the -173 G/C polymorphism of the macrophage migration inhibitory factor gene with ulcerative colitis. J Gastroenterol 39:242–246CrossRefPubMedGoogle Scholar
  61. Pakozdi A et al. (2006) Macrophage migration inhibitory factor: a mediator of matrix metal-loproteinase-2 production in rheumatoid arthritis. Arthritis Res Ther 8:R132CrossRefPubMedGoogle Scholar
  62. Parmar S, Platanias LC. (2005) Interferons. Cancer Treat Res 126:45–68CrossRefPubMedGoogle Scholar
  63. Petersen LR, Marfin AA. (2002) West Nile virus: a primer for the clinician. Ann Intern Med 137:173–179PubMedGoogle Scholar
  64. Pierson TC et al. (2005) An infectious West Nile virus that expresses a GFP reporter gene. Virology 334:28–40CrossRefPubMedGoogle Scholar
  65. Pisarev VB, Shishkina EO, Larichev VF, Grigor'eva NV. (2003) Morphofunctional characteristics of antigen-presenting cells in lymph node in mice with experimental West Nile fever. Bull Exp Biol Med 135:293–295CrossRefPubMedGoogle Scholar
  66. Radstake TR et al. (2005) Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum 52:3020–3029CrossRefPubMedGoogle Scholar
  67. Rawal A, Gavin PJ, Sturgis CD. (2006) Cerebrospinal fluid cytology in seasonal epidemic West Nile virus meningo-encephalitis. Diagn Cytopathol 34:127–129CrossRefPubMedGoogle Scholar
  68. Rios M et al. (2006) Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion. Transfusion 46:659–667CrossRefPubMedGoogle Scholar
  69. Saito T, Gale M Jr. (2007) Principles of intracellular viral recognition. Curr Opin Immunol 19:17–23CrossRefPubMedGoogle Scholar
  70. Samuel CE. (2002) Host genetic variability and West Nile virus susceptibility. Proc Natl Acad Sci USA 99:11555–11557CrossRefPubMedGoogle Scholar
  71. Samuel MA, Diamond MS. (2005) Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 79:13350–13361CrossRefPubMedGoogle Scholar
  72. Samuel MA, Diamond MS. (2006) Pathogenesis of West Nile Virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. J Virol 80:9349–9360CrossRefPubMedGoogle Scholar
  73. Samuel MA et al. (2006) PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons. J Virol 80:7009–7019CrossRefPubMedGoogle Scholar
  74. Scherbik SV, Paranjape JM, Stockman BM, Silverman RH, Brinton MA. (2006) RNase L plays a role in the antiviral response to West Nile virus. J Virol 80:2987–2999CrossRefPubMedGoogle Scholar
  75. Schroder K, Hertzog PJ, Ravasi T, Hume DA. (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189CrossRefPubMedGoogle Scholar
  76. Senter PD et al. (2002) Inhibition of macrophage migration inhibitory factor (MIF) tautomer-ase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci USA 99:144–149CrossRefPubMedGoogle Scholar
  77. Shirato K, Miyoshi H, Kariwa H, Takashima I. (2006) The kinetics of proinflammatory cytokines in murine peritoneal macrophages infected with envelope protein-glycosylated or non-glycosylated West Nile virus. Virus Res 121:11–16CrossRefPubMedGoogle Scholar
  78. Shrestha B, Samuel MA, Diamond MS. (2006a) CD8 + T cells require perforin to clear West Nile virus from infected neurons. J Virol 80:119–129CrossRefGoogle Scholar
  79. Shrestha B et-al.(2006b) Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection. J Virol 80:5338–5348CrossRefGoogle Scholar
  80. Silva MC, Guerrero-Plat A, Gilfoy FD, Garofalo RP, Mason PW. (2007) Differential activation of human monocyte-derived and plasmacytoid dendritic cells by West Nile virus generated in different host cells. J Virol 81:13640–13648CrossRefPubMedGoogle Scholar
  81. Srivastava S, Khanna N, Saxena SK, Singh A, Mathur A, Dhole TN. (1999) Degradation of Japanese encephalitis virus by neutrophils. Int J Exp Pathol 80:17–24CrossRefPubMedGoogle Scholar
  82. Steinman RM, Hemmi H. (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58CrossRefPubMedGoogle Scholar
  83. Takahashi K, Ip WE, Michelow IC, Ezekowitz RA. (2006) The mannose-binding lectin: a prototypic pattern recognition molecule. Curr Opin Immunol 18:16–23CrossRefPubMedGoogle Scholar
  84. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336CrossRefPubMedGoogle Scholar
  85. Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176:3804–3812PubMedGoogle Scholar
  86. Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK. (2006) CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis. Neurology 66:361–365CrossRefPubMedGoogle Scholar
  87. Vargin VV, Semenov BF. (1986) Changes of natural killer cell activity in different mouse lines by acute and asymptomatic flavivirus infections. Acta Virol 30:303–308PubMedGoogle Scholar
  88. Wang L, Das H, Kamath A, Bukowski JF. (2001) Human V gamma 2V delta 2 T cells produce IFN-gamma and TNF-alpha with an on/off/on cycling pattern in response to live bacterial products. J Immunol 167:6195–6201PubMedGoogle Scholar
  89. Wang T et al. (2003) IFN-gamma-producing gamma delta T cells help control murine West Nile virus infection. J Immunol 171:2524–2531PubMedGoogle Scholar
  90. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. (2004) Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10:1366–1373CrossRefPubMedGoogle Scholar
  91. Wang T et al. (2006) Gamma delta T cells facilitate adaptive immunity against West Nile virus infection in mice. J Immunol 177:1825–1832PubMedGoogle Scholar
  92. Yamamoto M et-al.(2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643CrossRefPubMedGoogle Scholar
  93. Yin Z et al. (2000) Dominance of IL-12 over IL-4 in gamma delta T cell differentiation leads to default production of IFN-gamma: failure to down-regulate IL-12 receptor beta 2-chain expression. J Immunol 164:3056–3064PubMedGoogle Scholar
  94. Yu X et al. (2007) Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. J Interferon Cytokine Res 27:103–109CrossRefPubMedGoogle Scholar
  95. Zhang W, Yue B, Wang GQ, Lu SL. (2002) Serum and ascites levels of macrophage migration inhibitory factor, TNF-alpha and IL-6 in patients with chronic virus hepatitis B and hepatitis cirrhosis. Hepatobiliary Pancreat Dis Int 1:577–5801PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Alvaro Arjona
    • 1
  • Erol Fikrig
    • 1
  1. 1.Section of Infectious Diseases – Department of Internal MedicineYale University School of MedicineNew HavenUSA

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