1932

Abstract

Flaviviruses are major emerging human pathogens on a global scale. Some flaviviruses can infect the central nervous system of the host and therefore are regarded as neurotropic. The most clinically relevant classical neurotropic flaviviruses include Japanese encephalitis virus, West Nile virus, and tick-borne encephalitis virus. In this review, we focus on these flaviviruses and revisit the concepts of flaviviral neurotropism, neuropathogenicity, neuroinvasion, and resultant neuropathogenesis. We attempt to synthesize the current knowledge about interactions between the central nervous system and flaviviruses from the neuroanatomical and neuropathological perspectives and address some misconceptions and controversies. We hope that revisiting these neuropathological concepts will improve the understanding of flaviviral neuroinfections. This, in turn, may provide further guiding foundations for relevant studies of other emerging or geographically expanding flaviviruses with neuropathogenic potential, such as Zika virus and dengue virus, and pave the way for intelligent therapeutic strategies harnessing potentially beneficial, protective host responses to interfere with disease progression and outcome.

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2018-09-29
2024-03-28
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Literature Cited

  1. 1.  Pierson TC, Diamond MS 2013. Flaviviruses. Fields Virology DM Knipe, PM Howley 747–94 Philadelphia: Lippincott Williams & Wilkins. , 6th ed..
    [Google Scholar]
  2. 2.  Gould EA, Solomon T 2008. Pathogenic flaviviruses. Lancet 371:500–9
    [Google Scholar]
  3. 3.  Gritsun TS, Nuttall PA, Gould EA 2003. Tick-borne flaviviruses. Adv. Virus Res. 61:317–71
    [Google Scholar]
  4. 4.  Sips GJ, Wilschut J, Smit JM 2012. Neuroinvasive flavivirus infections. Rev. Med. Virol. 22:69–87
    [Google Scholar]
  5. 5.  Labuda M, Austyn JM, Zuffova E, Kozuch O, Fuchsberger N et al. 1996. Importance of localized skin infection in tick-borne encephalitis virus transmission. Virology 219:357–66
    [Google Scholar]
  6. 6.  Lim PY, Behr MJ, Chadwick CM, Shi PY, Bernard KA 2011. Keratinocytes are cell targets of West Nile virus in vivo. J. Virol. 85:5197–201
    [Google Scholar]
  7. 7.  Garcia M, Wehbe M, Leveque N, Bodet C 2017. Skin innate immune response to flaviviral infection. Eur. Cytokine Netw. 28:41–51
    [Google Scholar]
  8. 8.  Johnston LJ, Halliday GM, King NJ 2000. Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus. J. Investig. Dermatol. 114:560–68
    [Google Scholar]
  9. 9.  Sejvar JJ 2007. The long-term outcomes of human West Nile virus infection. Clin. Infect. Dis. 44:1617–24
    [Google Scholar]
  10. 10.  Sejvar JJ 2014. Clinical manifestations and outcomes of West Nile virus infection. Viruses 6:606–23
    [Google Scholar]
  11. 11.  Davis LE, DeBiasi R, Goade DE, Haaland KY, Harrington JA et al. 2006. West Nile virus neuroinvasive disease. Ann. Neurol. 60:286–300
    [Google Scholar]
  12. 12.  Gyure KA 2009. West Nile virus infections. J. Neuropathol. Exp. Neurol. 68:1053–60
    [Google Scholar]
  13. 13.  Griffiths MJ, Turtle L, Solomon T 2014. Japanese encephalitis virus infection. Handb. Clin. Neurol. 123:561–76
    [Google Scholar]
  14. 14.  Sejvar JJ 2016. West Nile virus infection. Emerging Infections 10 W Scheld, J Hughes, R Whitley 175–99 Washington, DC: ASM Press https://doi.org/10.1128/microbiolspec.EI10-0021-2016
    [Crossref] [Google Scholar]
  15. 15.  Turtle L, Griffiths MJ, Solomon T 2012. Encephalitis caused by flaviviruses. QJM 105:219–23
    [Google Scholar]
  16. 16.  Lasala PR, Holbrook M 2010. Tick-borne flaviviruses. Clin. Lab. Med. 30:221–35
    [Google Scholar]
  17. 17.  Albrecht P 1968. Pathogenesis of neurotropic arbovirus infections. Curr. Top. Microbiol. Immunol. 43:44–91
    [Google Scholar]
  18. 18.  Chambers TJ, Diamond MS 2003. Pathogenesis of flavivirus encephalitis. Adv. Virus Res. 60:273–342
    [Google Scholar]
  19. 19.  Monath TP 1986. Pathology of the flaviviruses. The Togaviridae and Flaviviridae S Schlesinger, MJ Schlesinger 375–440 New York: Plenum
    [Google Scholar]
  20. 20.  Omalu BI, Shakir AA, Wang G, Lipkin WI, Wiley CA 2003. Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus. Brain Pathol 13:465–72
    [Google Scholar]
  21. 21.  Gelpi E, Preusser M, Garzuly F, Holzmann H, Heinz FX, Budka H 2005. Visualization of Central European tick-borne encephalitis infection in fatal human cases. J. Neuropathol. Exp. Neurol. 64:506–12
    [Google Scholar]
  22. 22.  Gelpi E, Preusser M, Laggner U, Garzuly F, Holzmann H et al. 2006. Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue. J. Neurovirol. 12:322–27
    [Google Scholar]
  23. 23.  Johnson RT, Burke DS, Elwell M, Leake CJ, Nisalak A et al. 1985. Japanese encephalitis: immunocytochemical studies of viral antigen and inflammatory cells in fatal cases. Ann. Neurol. 18:567–73
    [Google Scholar]
  24. 24.  Guarner J, Shieh WJ, Hunter S, Paddock CD, Morken T et al. 2004. Clinicopathologic study and laboratory diagnosis of 23 cases with West Nile virus encephalomyelitis. Hum. Pathol. 35:983–90
    [Google Scholar]
  25. 25.  Miner JJ, Diamond MS 2017. Zika virus pathogenesis and tissue tropism. Cell Host Microbe 21:134–42
    [Google Scholar]
  26. 26.  Puccioni-Sohler M, Rosadas C 2015. Advances and new insights in the neuropathogenesis of dengue infection. Arq. Neuropsiquiatr. 73:698–703
    [Google Scholar]
  27. 27.  Carod-Artal FJ, Wichmann O, Farrar J, Gascon J 2013. Neurological complications of dengue virus infection. Lancet Neurol 12:906–19
    [Google Scholar]
  28. 28.  Koyuncu OO, Hogue IB, Enquist LW 2013. Virus infections in the nervous system. Cell Host Microbe 13:379–93
    [Google Scholar]
  29. 29.  Griffin DE 2003. Immune responses to RNA-virus infections of the CNS. Nat. Rev. Immunol. 3:493–502
    [Google Scholar]
  30. 30.  Gosztonyi G, Koprowski H 2001. The concept of neurotropism and selective vulnerability (“pathoclisis”) in virus infections of the nervous system—a historical overview. Curr. Top. Microbiol. Immunol. 253:1–13
    [Google Scholar]
  31. 31.  Lindenbach BD, Murray CL, Thiel HJ, Rice CM 2013. Flaviviridae. Fields Virology DM Knipe, PM Howley 712–46 Philadelphia: Lippincott Williams & Wilkins. , 6th ed..
    [Google Scholar]
  32. 32.  Fernandez-Garcia MD, Mazzon M, Jacobs M, Amara A 2009. Pathogenesis of flavivirus infections: using and abusing the host cell. Cell Host Microbe 5:318–28
    [Google Scholar]
  33. 33.  Nagata N, Iwata-Yoshikawa N, Hayasaka D, Sato Y, Kojima A et al. 2015. The pathogenesis of 3 neurotropic flaviviruses in a mouse model depends on the route of neuroinvasion after viremia. J. Neuropathol. Exp. Neurol. 74:250–60
    [Google Scholar]
  34. 34.  Nathanson N 2014. Viral neuropathogenesis. Handb. Clin. Neurol. 123:175–91
    [Google Scholar]
  35. 35.  Hurrelbrink RJ, McMinn PC 2003. Molecular determinants of virulence: the structural and functional basis for flavivirus attenuation. Adv. Virus Res. 60:1–42
    [Google Scholar]
  36. 36.  Cho H, Diamond MS 2012. Immune responses to West Nile virus infection in the central nervous system. Viruses 4:3812–30
    [Google Scholar]
  37. 37.  Diamond MS, Gale M Jr 2012. Cell-intrinsic innate immune control of West Nile virus infection. Trends Immunol 33:522–30
    [Google Scholar]
  38. 38.  Diamond MS, Mehlhop E, Oliphant T, Samuel MA 2009. The host immunologic response to West Nile encephalitis virus. Front. Biosci. 14:3024–34
    [Google Scholar]
  39. 39.  Diamond MS, Shrestha B, Mehlhop E, Sitati E, Engle M 2003. Innate and adaptive immune responses determine protection against disseminated infection by West Nile encephalitis virus. Viral Immunol 16:259–78
    [Google Scholar]
  40. 40.  Klein RS, Diamond MS 2008. Immunological headgear: Antiviral immune responses protect against neuroinvasive West Nile virus. Trends Mol. Med. 14:286–94
    [Google Scholar]
  41. 41.  Suthar MS, Diamond MS, Gale M Jr 2013. West Nile virus infection and immunity. Nat. Rev. Microbiol. 11:115–28
    [Google Scholar]
  42. 42.  Quicke KM, Suthar MS 2013. The innate immune playbook for restricting West Nile virus infection. Viruses 5:2643–58
    [Google Scholar]
  43. 43.  Salinas S, Schiavo G, Kremer EJ 2010. A hitchhiker's guide to the nervous system: the complex journey of viruses and toxins. Nat. Rev. Microbiol. 8:645–55
    [Google Scholar]
  44. 44.  Kristensson K 2011. Microbes’ roadmap to neurons. Nat. Rev. Neurosci. 12:345–57
    [Google Scholar]
  45. 45.  Suen WW, Prow NA, Hall RA, Bielefeldt-Ohmann H 2014. Mechanism of West Nile virus neuroinvasion: a critical appraisal. Viruses 6:2796–825
    [Google Scholar]
  46. 46.  Fredericksen BL 2014. The neuroimmune response to West Nile virus. J. Neurovirol. 20:113–21
    [Google Scholar]
  47. 47.  Morrey JD, Olsen AL, Siddharthan V, Motter NE, Wang H et al. 2008. Increased blood-brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents. J. Gen. Virol. 89:467–73
    [Google Scholar]
  48. 48.  Ruzek D, Salat J, Singh SK, Kopecky J 2011. Breakdown of the blood-brain barrier during tick-borne encephalitis in mice is not dependent on CD8+ T-cells. PLOS ONE 6:e20472
    [Google Scholar]
  49. 49.  Li F, Wang Y, Yu L, Cao S, Wang K et al. 2015. Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection. J. Virol. 89:5602–14
    [Google Scholar]
  50. 50.  Dai J, Wang P, Bai F, Town T, Fikrig E 2008. ICAM-1 participates in the entry of West Nile virus into the central nervous system. J. Virol. 82:4164–68
    [Google Scholar]
  51. 51.  Wang S, Welte T, McGargill M, Town T, Thompson J et al. 2008. Drak2 contributes to West Nile virus entry into the brain and lethal encephalitis. J. Immunol. 181:2084–91
    [Google Scholar]
  52. 52.  Wang P, Dai J, Bai F, Kong KF, Wong SJ et al. 2008. Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain. J. Virol. 82:8978–85
    [Google Scholar]
  53. 53.  Palus M, Vancova M, Sirmarova J, Elsterova J, Perner J, Ruzek D 2017. Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood-brain barrier integrity. Virology 507:110–22
    [Google Scholar]
  54. 54.  Hussmann KL, Samuel MA, Kim KS, Diamond MS, Fredericksen BL 2013. Differential replication of pathogenic and nonpathogenic strains of West Nile virus within astrocytes. J. Virol. 87:2814–22
    [Google Scholar]
  55. 55.  Liou ML, Hsu CY 1998. Japanese encephalitis virus is transported across the cerebral blood vessels by endocytosis in mouse brain. Cell Tissue Res 293:389–94
    [Google Scholar]
  56. 56.  Bai F, Kong KF, Dai J, Qian F, Zhang L et al. 2010. A paradoxical role for neutrophils in the pathogenesis of West Nile virus. J. Infect. Dis. 202:1804–12
    [Google Scholar]
  57. 57.  Bechmann I, Galea I, Perry VH 2007. What is the blood-brain barrier (not)?. Trends Immunol 28:5–11
    [Google Scholar]
  58. 58.  Dyrna F, Hanske S, Krueger M, Bechmann I 2013. The blood-brain barrier. J. Neuroimmune Pharmacol. 8:763–73
    [Google Scholar]
  59. 59.  Engelhardt B, Ransohoff RM 2005. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485–95
    [Google Scholar]
  60. 60.  Engelhardt B, Ransohoff RM 2012. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33:579–89
    [Google Scholar]
  61. 61.  Maximova OA, Faucette LJ, Ward JM, Murphy BR, Pletnev AG 2009. Cellular inflammatory response to flaviviruses in the central nervous system of a primate host. J. Histochem. Cytochem. 57:973–89
    [Google Scholar]
  62. 62.  Schwerk C, Tenenbaum T, Kim KS, Schroten H 2015. The choroid plexus—a multi-role player during infectious diseases of the CNS. Front. Cell. Neurosci. 9:80
    [Google Scholar]
  63. 63.  Samuel MA, Wang H, Siddharthan V, Morrey JD, Diamond MS 2007. Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. PNAS 104:17140–45
    [Google Scholar]
  64. 64.  Wang H, Siddharthan V, Hall JO, Morrey JD 2009. West Nile virus preferentially transports along motor neuron axons after sciatic nerve injection of hamsters. J. Neurovirol. 15:293–99
    [Google Scholar]
  65. 65.  Harrison AK, Murphy FA, Gardner JJ 1982. Visceral target organs in systemic St. Louis encephalitis virus infection of hamsters. Exp. Mol. Pathol. 37:292–304
    [Google Scholar]
  66. 66.  Faber HK, Gebhardt LP 1933. Localizations of the virus of poliomyelitis in the central nervous system during the preparalytic period, after intranasal instillation. J. Exp. Med. 57:933–54
    [Google Scholar]
  67. 67.  Brown AN, Kent KA, Bennett CJ, Bernard KA 2007. Tissue tropism and neuroinvasion of West Nile virus do not differ for two mouse strains with different survival rates. Virology 368:422–30
    [Google Scholar]
  68. 68.  Monath TP, Cropp CB, Harrison AK 1983. Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy. Lab. Investig. 48:399–410
    [Google Scholar]
  69. 69.  Nir Y, Beemer A, Goldwasser RA 1965. West Nile virus infection in mice following exposure to a viral aerosol. Br. J. Exp. Pathol. 46:443–49
    [Google Scholar]
  70. 70.  McMinn PC, Dalgarno L, Weir RC 1996. A comparison of the spread of Murray Valley encephalitis viruses of high or low neuroinvasiveness in the tissues of Swiss mice after peripheral inoculation. Virology 220:414–23
    [Google Scholar]
  71. 71.  Yamada M, Nakamura K, Yoshii M, Kaku Y, Narita M 2009. Brain lesions induced by experimental intranasal infection of Japanese encephalitis virus in piglets. J. Comp. Pathol. 141:156–62
    [Google Scholar]
  72. 72.  Kalinke U, Bechmann I, Detje CN 2011. Host strategies against virus entry via the olfactory system. Virulence 2:367–70
    [Google Scholar]
  73. 73.  Durrant DM, Ghosh S, Klein RS 2016. The olfactory bulb: an immunosensory effector organ during neurotropic viral infections. ACS Chem. Neurosci. 7:464–69
    [Google Scholar]
  74. 74.  Kurhade C, Zegenhagen L, Weber E, Nair S, Michaelsen-Preusse K et al. 2016. Type I interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1. J. Neuroinflamm. 13:22
    [Google Scholar]
  75. 75.  Pedrosa PB, Cardoso TA 2011. Viral infections in workers in hospital and research laboratory settings: a comparative review of infection modes and respective biosafety aspects. Int. J. Infect. Dis. 15:e366–76
    [Google Scholar]
  76. 76.  van Marle G, Antony J, Ostermann H, Dunham C, Hunt T et al. 2007. West Nile virus-induced neuroinflammation: glial infection and capsid protein-mediated neurovirulence. J. Virol. 81:10933–49
    [Google Scholar]
  77. 77.  Maximova OA, Bernbaum JG, Pletnev AG 2016. West Nile virus spreads transsynaptically within the pathways of motor control: anatomical and ultrastructural mapping of neuronal virus infection in the primate central nervous system. PLOS Negl. Trop. Dis. 10:e0004980
    [Google Scholar]
  78. 78.  Carty M, Reinert L, Paludan SR, Bowie AG 2014. Innate antiviral signalling in the central nervous system. Trends Immunol 35:79–87
    [Google Scholar]
  79. 79.  Nair S, Diamond MS 2015. Innate immune interactions within the central nervous system modulate pathogenesis of viral infections. Curr. Opin. Immunol. 36:47–53
    [Google Scholar]
  80. 80.  Carrithers MD 2014. Innate immune viral recognition: relevance to CNS infections. Handb. Clin. Neurol. 123:215–23
    [Google Scholar]
  81. 81.  Bardina SV, Lim JK 2012. The role of chemokines in the pathogenesis of neurotropic flaviviruses. Immunol. Res. 54:121–32
    [Google Scholar]
  82. 82.  Ransohoff RM, Brown MA 2012. Innate immunity in the central nervous system. J. Clin. Investig. 122:1164–71
    [Google Scholar]
  83. 83.  Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M et al. 2004. Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17:942–64
    [Google Scholar]
  84. 84.  Hanisch UK, Kettenmann H 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10:1387–94
    [Google Scholar]
  85. 85.  Kettenmann H, Hanisch UK, Noda M, Verkhratsky A 2011. Physiology of microglia. Physiol. Rev. 91:461–553
    [Google Scholar]
  86. 86.  Colonna M, Butovsky O 2017. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35:441–68
    [Google Scholar]
  87. 87.  Thongtan T, Thepparit C, Smith DR 2012. The involvement of microglial cells in Japanese encephalitis infections. Clin. Dev. Immunol. 2012:890586
    [Google Scholar]
  88. 88.  Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B et al. 2016. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:538–43
    [Google Scholar]
  89. 89.  Quick ED, Leser JS, Clarke P, Tyler KL 2014. Activation of intrinsic immune responses and microglial phagocytosis in an ex vivo spinal cord slice culture model of West Nile virus infection. J. Virol. 88:13005–14
    [Google Scholar]
  90. 90.  Szretter KJ, Samuel MA, Gilfillan S, Fuchs A, Colonna M, Diamond MS 2009. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile virus pathogenesis. J. Virol. 83:9329–38
    [Google Scholar]
  91. 91.  Chen Z, Trapp BD 2016. Microglia and neuroprotection. J. Neurochem. 136:Suppl. 110–17
    [Google Scholar]
  92. 92.  Sofroniew MV, Vinters HV 2010. Astrocytes: biology and pathology. Acta Neuropathol 119:7–35
    [Google Scholar]
  93. 93.  Kimelberg HK 2010. Functions of mature mammalian astrocytes: a current view. Neuroscientist 16:79–106
    [Google Scholar]
  94. 94.  Abbott NJ 2002. Astrocyte-endothelial interactions and blood-brain barrier permeability. J. Anat. 200:629–38
    [Google Scholar]
  95. 95.  Farina C, Aloisi F, Meinl E 2007. Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–45
    [Google Scholar]
  96. 96.  Diniz JA, Da Rosa AP, Guzman H, Xu F, Xiao SY et al. 2006. West Nile virus infection of primary mouse neuronal and neuroglial cells: the role of astrocytes in chronic infection. Am. J. Trop. Med. Hyg. 75:691–96
    [Google Scholar]
  97. 97.  Mishra MK, Koli P, Bhowmick S, Basu A 2007. Neuroprotection conferred by astrocytes is insufficient to protect animals from succumbing to Japanese encephalitis. Neurochem. Int. 50:764–73
    [Google Scholar]
  98. 98.  Blakely PK, Kleinschmidt-DeMasters BK, Tyler KL, Irani DN 2009. Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection. J. Neuropathol. Exp. Neurol. 68:1061–72
    [Google Scholar]
  99. 99.  Verma S, Kumar M, Gurjav U, Lum S, Nerurkar VR 2010. Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor. Virology 397:130–38
    [Google Scholar]
  100. 100.  Palus M, Bily T, Elsterova J, Langhansova H, Salat J et al. 2014. Infection and injury of human astrocytes by tick-borne encephalitis virus. J. Gen. Virol. 95:2411–26
    [Google Scholar]
  101. 101.  Lindqvist R, Mundt F, Gilthorpe JD, Wolfel S, Gekara NO et al. 2016. Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. J. Neuroinflamm. 13:277
    [Google Scholar]
  102. 102.  Daniels BP, Jujjavarapu H, Durrant DM, Williams JL, Green RR et al. 2017. Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J. Clin. Investig. 127:843–56
    [Google Scholar]
  103. 103.  van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis JN 2018. Zika virus targeting in the developing brain. J. Neurosci. 37:2161–75
    [Google Scholar]
  104. 104.  Cserr HF, Harling-Berg CJ, Knopf PM 1992. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–76
    [Google Scholar]
  105. 105.  Galea I, Bechmann I, Perry VH 2007. What is immune privilege (not)?. Trends Immunol 28:12–18
    [Google Scholar]
  106. 106.  Ransohoff RM, Kivisakk P, Kidd G 2003. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3:569–81
    [Google Scholar]
  107. 107.  Ransohoff RM, Engelhardt B 2012. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12:623–35
    [Google Scholar]
  108. 108.  Engelhardt B, Carare RO, Bechmann I, Flugel A, Laman JD, Weller RO 2016. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol 132:317–38
    [Google Scholar]
  109. 109.  Raper D, Louveau A, Kipnis J 2016. How do meningeal lymphatic vessels drain the CNS?. Trends Neurosci 39:581–86
    [Google Scholar]
  110. 110.  Louveau A, Harris TH, Kipnis J 2015. Revisiting the mechanisms of CNS immune privilege. Trends Immunol 36:569–77
    [Google Scholar]
  111. 111.  Maximova OA, Speicher JM, Skinner JR, Murphy BR, St. Claire MC et al. 2014. Assurance of neuroattenuation of a live vaccine against West Nile virus: a comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4Δ30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine. Vaccine 32:3187–97
    [Google Scholar]
  112. 112.  Maximova OA, Ward JM, Asher DM, St. Claire M, Finneyfrock BW et al. 2008. Comparative neuropathogenesis and neurovirulence of attenuated flaviviruses in nonhuman primates. J. Virol. 82:5255–68
    [Google Scholar]
  113. 113.  Libbey JE, Fujinami RS 2014. Adaptive immune response to viral infections in the central nervous system. Handb. Clin. Neurol. 123:225–47
    [Google Scholar]
  114. 114.  Owens T, Bechmann I, Engelhardt B 2008. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67:1113–21
    [Google Scholar]
  115. 115.  Dorrbecker B, Dobler G, Spiegel M, Hufert FT 2010. Tick-borne encephalitis virus and the immune response of the mammalian host. Travel Med. Infect. Dis. 8:213–22
    [Google Scholar]
  116. 116.  Netland J, Bevan MJ 2013. CD8 and CD4 T cells in West Nile virus immunity and pathogenesis. Viruses 5:2573–84
    [Google Scholar]
  117. 117.  Binder GK, Griffin DE 2001. Interferon-γ-mediated site-specific clearance of alphavirus from CNS neurons. Science 293:303–6
    [Google Scholar]
  118. 118.  Dörries R 2001. The role of T-cell-mediated mechanisms in virus infections of the nervous system. The Mechanisms of Neuronal Damage in Virus Infections of the Nervous System G Gosztonyi 219–45 Berlin: Springer
    [Google Scholar]
  119. 119.  Armah HB, Wang G, Omalu BI, Tesh RB, Gyure KA et al. 2007. Systemic distribution of West Nile virus infection: postmortem immunohistochemical study of six cases. Brain Pathol 17:354–62
    [Google Scholar]
  120. 120.  Tschen SI, Stohlman SA, Ramakrishna C, Hinton DR, Atkinson RD, Bergmann CC 2006. CNS viral infection diverts homing of antibody-secreting cells from lymphoid organs to the CNS. Eur. J. Immunol. 36:603–12
    [Google Scholar]
  121. 121.  Aguzzi A, Barres BA, Bennett ML 2013. Microglia: scapegoat, saboteur, or something else?. Science 339:156–61
    [Google Scholar]
  122. 122.  Nimmerjahn A, Kirchhoff F, Helmchen F 2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–18
    [Google Scholar]
  123. 123.  Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J 2009. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29:3974–80
    [Google Scholar]
  124. 124.  Tremblay ME, Lowery RL, Majewska AK 2010. Microglial interactions with synapses are modulated by visual experience. PLOS Biol 8:e1000527
    [Google Scholar]
  125. 125.  Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A 2011. The role of microglia in the healthy brain. J. Neurosci. 31:16064–69
    [Google Scholar]
  126. 126.  Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y et al. 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8:752–58
    [Google Scholar]
  127. 127.  Kettenmann H, Kirchhoff F, Verkhratsky A 2013. Microglia: new roles for the synaptic stripper. Neuron 77:10–18
    [Google Scholar]
  128. 128.  Biber K, Owens T, Boddeke E 2014. What is microglia neurotoxicity (not)?. Glia 62:841–54
    [Google Scholar]
  129. 129.  Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X et al. 2007. Evidence for synaptic stripping by cortical microglia. Glia 55:360–68
    [Google Scholar]
  130. 130.  Graeber MB 2010. Changing face of microglia. Science 330:783–88
    [Google Scholar]
  131. 131.  Spector R, Snodgrass SR, Johanson CE 2015. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp. Neurol. 273:57–68
    [Google Scholar]
  132. 132.  Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ 2010. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37:13–25
    [Google Scholar]
  133. 133.  Broadwell RD, Sofroniew MV 1993. Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system. Exp. Neurol. 120:245–63
    [Google Scholar]
  134. 134.  Spector R, Keep RF, Snodgrass SR, Smith QR, Johanson CE 2015. A balanced view of choroid plexus structure and function: focus on adult humans. Exp. Neurol. 267:78–86
    [Google Scholar]
  135. 135.  Duvernoy HM, Risold PY 2007. The circumventricular organs: an atlas of comparative anatomy and vascularization. Brain Res. Rev. 56:119–47
    [Google Scholar]
  136. 136.  Wolburg H, Paulus W 2010. Choroid plexus: biology and pathology. Acta Neuropathol 119:75–88
    [Google Scholar]
  137. 137.  Choi I, Lee S, Hong YK 2012. The new era of the lymphatic system: no longer secondary to the blood vascular system. Cold Spring Harb. Perspect. Med. 2:a006445
    [Google Scholar]
  138. 138.  Harling-Berg CJ, Park TJ, Knopf PM 1999. Role of the cervical lymphatics in the Th2-type hierarchy of CNS immune regulation. J. Neuroimmunol. 101:111–27
    [Google Scholar]
  139. 139.  Krueger M, Bechmann I 2010. CNS pericytes: concepts, misconceptions, and a way out. Glia 58:1–10
    [Google Scholar]
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