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CNS infection and immune privilege


Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNS infections and ask whether immune privilege may provide protection for certain pathogens and promote their latency.

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Fig. 1: Immune cell traffic through the CNS.
Fig. 2: Pathogen entry into the CNS parenchyma.
Fig. 3: Cells and sites of CNS latent infection.


  1. 1.

    Miller, K. D., Schnell, M. J. & Rall, G. F. Keeping it in check: chronic viral infection and antiviral immunity in the brain. Nat. Rev. Neurosci. 17, 766–776 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    CAS  Google Scholar 

  3. 3.

    Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nature Immunol. 18, 123–131 (2017). This review emphasizes the importance of the CNS anatomy and its lymphatic connections with the peripheral lymphoid system in order to understand the nature of CNS IP.

    CAS  Google Scholar 

  5. 5.

    Klein, R. S. & Hunter, C. A. Protective and pathological immunity during central nervous system infections. Immunity 46, 891–909 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Spadoni, I., Fornasa, G. & Rescigno, M. Organ-specific protection mediated by cooperation between vascular and epithelial barriers. Nat. Rev. Immunol. 17, 761–773 (2017).

    CAS  PubMed  Google Scholar 

  7. 7.

    Medawar, P. B. Immunity to homolgous grafted skin. Br. J. Exp. Pathol. 29, 58–69 (1948).

    CAS  Google Scholar 

  8. 8.

    Baruch, K. & Schwartz, M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34, 11–16 (2013).

    CAS  PubMed  Google Scholar 

  9. 9.

    Dando, S. J., Naranjo Golborne, C., Chinnery, H. R., Ruitenberg, M. J. & McMenamin, P. G. A case of mistaken identity: CD11c-eYFP cells in the normal mouse brain parenchyma and neural retina display the phenotype of microglia, not dendritic cells. Glia 64, 1331–1349 (2016).

    PubMed  Google Scholar 

  10. 10.

    Forrester, J. V., Xu, H., Kuffova, L., Dick, A. D. & McMenamin, P. G. Dendritic cell physiology and function in the eye. Immunol. Rev. 234, 282–304 (2010).

    CAS  PubMed  Google Scholar 

  11. 11.

    Kida, S., Steart, P. V., Zhang, E. T. & Weller, R. O. Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages. Acta Neuropathol. 85, 646–652 (1993).

    CAS  PubMed  Google Scholar 

  12. 12.

    Coles, J. A., Myburgh, E., Brewer, J. M. & McMenamin, P. G. Where are we? The anatomy of the murine cortical meninges revisited for intravital imaging, immunology, and clearance of waste from the brain. Prog. Neurobiol. 156, 107–148 (2017).

    PubMed  Google Scholar 

  13. 13.

    Belanger, M., Allaman, I. & Magistretti, P. J. Brain energy metabolism: focus on astrocyte–neuron metabolic cooperation. Cell Metab. 14, 724–738 (2011).

    CAS  PubMed  Google Scholar 

  14. 14.

    Ryan, D. G. & O’Neill, L. A. J. Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett. 591, 2992–3006 (2017).

    CAS  PubMed  Google Scholar 

  15. 15.

    Caspi, R. R. Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006). This paper is one of the first to argue for a re-evaluation of the benefits of CNS IP and the risks it carries as an immune defence mechanism.

    PubMed  Google Scholar 

  16. 16.

    Forrester, J. V., Xu, H., Lambe, T. & Cornall, R. Immune privilege or privileged immunity? Mucosal Immunol. 1, 372–381 (2008).

    CAS  PubMed  Google Scholar 

  17. 17.

    Niederkorn, J. Y. & Stein-Streilein, J. History and physiology of immune privilege. Ocular Immunol. Inflamm. 18, 19–23 (2010).

    Google Scholar 

  18. 18.

    Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat. Rev. Immunol. 3, 879–889 (2003).

    CAS  PubMed  Google Scholar 

  19. 19.

    Taylor, A. W. Ocular immune privilege and transplantation. Front. Immunol. 7, 37 (2016).

    Google Scholar 

  20. 20.

    Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).

    CAS  PubMed  Google Scholar 

  21. 21.

    Huber, A. K. & Irani, D. N. Is the concept of central nervous system immune privilege irrelevant in the setting of acute infection? Front. Oncol. 5, 99 (2015).

    Google Scholar 

  22. 22.

    Solomos, A. C. & Rall, G. Get it through your thick head: emerging principles in neuroimmunology and neurovirology redefine central nervous system “immune privilege”. ACS Chem. Neurosci. 20, 435–441 (2016).

    Google Scholar 

  23. 23.

    Baaten, B. J., Cooper, A. M., Swain, S. L. & Bradley, L. M. Location, location, location: the impact of migratory heterogeneity on T cell function. Front. Immunol. 4, 311 (2013).

    Google Scholar 

  24. 24.

    Sitkovsky, M. V. et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22, 657–682 (2004).

    CAS  PubMed  Google Scholar 

  25. 25.

    Yanagida, K. et al. Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc. Natl Acad. Sci. USA 114, 4531–4536 (2017).

    CAS  PubMed  Google Scholar 

  26. 26.

    Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13–25 (2010).

    CAS  PubMed  Google Scholar 

  27. 27.

    Luethy, L. N. et al. Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system. Virology 487, 1–10 (2016).

    CAS  PubMed  Google Scholar 

  28. 28.

    Reuter, J. D., Gomez, D. L., Wilson, J. H. & Van Den Pol, A. N. Systemic immune deficiency necessary for cytomegalovirus invasion of the mature brain. J. Virol. 78, 1473–1487 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kawasaki, H. et al. Cytomegalovirus initiates infection selectively from high-level β1 integrin-expressing cells in the brain. Am. J. Pathol. 185, 1304–1323 (2015). References 28 and 29 demonstrate the relationship risk of CMV infection in the brain and immunodeficiency, in the latter case due to incomplete maturation of the neonatal immune system and underdevelopment of the BBB.

    CAS  PubMed  Google Scholar 

  30. 30.

    Domev, H., Milkov, I., Itskovitz-Eldor, J. & Dar, A. Immunoevasive pericytes from human pluripotent stem cells preferentially modulate induction of allogeneic regulatory T cells. Stem Cells Transl Med. 3, 1169–1181 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Hill, J., Rom, S., Ramirez, S. H. & Persidsky, Y. Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease. J. Neuroimmune Pharmacol. 9, 591–605 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Iizuka-Koga, M. et al. Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications. J. Autoimmun. 83, 113–121 (2017).

    CAS  PubMed  Google Scholar 

  33. 33.

    Coureuil, M., Lecuyer, H., Bourdoulous, S. & Nassif, X. A journey into the brain: insight into how bacterial pathogens cross blood-brain barriers. Nat. Rev. Microbiol. 15, 149–159 (2017).

    CAS  PubMed  Google Scholar 

  34. 34.

    Faraco, G., Park, L., Anrather, J. & Iadecola, C. Brain perivascular macrophages: characterization and functional roles in health and disease. J. Mol. Med. 95, 1143–1152 (2017).

    CAS  Google Scholar 

  35. 35.

    Nau, R., Ribes, S., Djukic, M. & Eiffert, H. Strategies to increase the activity of microglia as efficient protectors of the brain against infections. Front. Cell. Neurosci. 8, 138 (2014).

    Google Scholar 

  36. 36.

    Mishra, M. K. & Yong, V. W. Myeloid cells — targets of medication in multiple sclerosis. Nat. Rev. Neurol. 12, 539–551 (2016).

    CAS  PubMed  Google Scholar 

  37. 37.

    Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Pizzo, M. E. et al. Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery. J. Physiol. 596, 445–475 (2018).

    CAS  PubMed  Google Scholar 

  40. 40.

    Wostyn, P., Killer, H. E. & De Deyn, P. P. Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma. Clin. Exp. Ophthalmol. 45, 539–547 (2017).

    PubMed  Google Scholar 

  41. 41.

    Banerji, S. et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789–801 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Harwood, N. E. & Batista, F. D. The antigen expressway: follicular conduits carry antigen to B cells. Immunity 30, 177–179 (2009).

    CAS  PubMed  Google Scholar 

  44. 44.

    Burdo, T. H., Lackner, A. & Williams, K. C. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol. Rev. 254, 102–113 (2013).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523 (2009).

    CAS  Google Scholar 

  46. 46.

    Robert, R. et al. Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice. JCI Insight. (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Kida, S., Pantazis, A. & Weller, R. O. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19, 480–488 (1993).

    CAS  PubMed  Google Scholar 

  48. 48.

    Mohammad, M. G. et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Invest. 124, 1228–1241 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Cserr, H. F., Harling-Berg, C. J. & Knopf, P. M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 2, 269–276 (1992). This paper presents the first definitive report showing that the CNS communicates with secondary lymphoid organs — in this case, the deep cervical lymph nodes.

    CAS  PubMed  Google Scholar 

  51. 51.

    Raper, D., Louveau, A. & Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 39, 581–586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Dando, S. J. et al. Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin. Microbiol. Rev. 27, 691–726 (2014). This article provides a comprehensive review of the various routes through which pathogens gain access to the CNS parenchyma.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 16, 877–897 (2017).

    Google Scholar 

  54. 54.

    Orihuela, C. J. et al. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J. Clin. Invest. 119, 1638–1646 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Iovino, F. et al. pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion. J. Exp. Med. 214, 1619–1630 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Radin, J. N. et al. β-Arrestin 1 participates in platelet-activating factor receptor-mediated endocytosis of Streptococcus pneumoniae. Infect. Immun. 73, 7827–7835 (2005).

    CAS  Google Scholar 

  57. 57.

    Loh, L. N., Gao, G. & Tuomanen, E. I. Dissecting bacterial cell wall entry and signaling in eukaryotic cells: an actin-dependent pathway parallels platelet-activating factor receptor-mediated endocytosis. mBio 8, e02030–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Liou, M. L. & Hsu, C. Y. Japanese encephalitis virus is transported across the cerebral blood vessels by endocytosis in mouse brain. Cell Tissue Res. 293, 389–394 (1998).

    CAS  PubMed  Google Scholar 

  59. 59.

    Mathur, A., Khanna, N. & Chaturvedi, U. C. Breakdown of blood-brain barrier by virus-induced cytokine during Japanese encephalitis virus infection. Int. J. Exp. Pathol. 73, 603–611 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Li, F. et al. Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection. J. Virol. 89, 5602–5614 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ahmed, W., Zheng, K. & Liu, Z. F. Establishment of chronic infection: Brucella’s stealth strategy. Front. Cell. Infect. Microbiol. (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Allwood, E. M., Devenish, R. J., Prescott, M., Adler, B. & Boyce, J. D. Strategies for intracellular survival of Burkholderia pseudomallei. Front. Microbiol. (2011).

    Article  Google Scholar 

  63. 63.

    Quigley, J. et al. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis. mBio 8, e00148–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Ruan, Y., Rezelj, S., Bedina Zavec, A., Anderluh, G. & Scheuring, S. Listeriolysin O membrane damaging activity involves arc formation and lineaction — implication for Listeria monocytogenes escape from phagocytic vacuole. PLOS Pathog. 12, e1005597 (2016).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Altan-Bonnet, N. Extracellular vesicles are the Trojan horses of viral infection. Curr. Opin. Microbiol. 32, 77–81 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Santiago-Tirado, F. H., Onken, M. D., Cooper, J. A., Klein, R. S. & Doering, T. L. Trojan horse transit contributes to blood-brain barrier crossing of a eukaryotic pathogen. mBio 8, e02183–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Weidner, J. M. et al. Migratory activation of parasitized dendritic cells by the protozoan Toxoplasma gondii 14-3-3 protein. Cell. Microbiol. 18, 1537–1550 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Konradt, C. et al. Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system. Nat. Microbiol. 1, 16001 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Chen, Y. S. et al. Involvement of L-selectin expression in Burkholderia pseudomallei-infected monocytes invading the brain during murine melioidosis. Virulence 8, 751–766 (2017).

    CAS  PubMed  Google Scholar 

  70. 70.

    Silveira, C. et al. Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis. Br. J. Ophthalmol. 95, 396–400 (2011).

    PubMed  Google Scholar 

  71. 71.

    Goodrum, F. Human cytomegalovirus latency: approaching the gordian knot. Annu. Rev. Virol. 3, 333–357 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Goodrum, F. D., Jordan, C. T., High, K. & Shenk, T. Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc. Natl Acad. Sci. USA 99, 16255–16260 (2002).

    CAS  PubMed  Google Scholar 

  73. 73.

    Fujimoto, T. et al. Choroidal neovascularization enhanced by Chlamydia pneumoniae via Toll-like receptor 2 in the retinal pigment epithelium. Investigative Ophthalmol. Visual Sci. 51, 4694–4702 (2010).

    Google Scholar 

  74. 74.

    Miles, B. et al. Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen. J. Leukocyte Biol. 94, 281–289 (2013).

    CAS  PubMed  Google Scholar 

  75. 75.

    Wolf, A. J. et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J. Immunol. 179, 2509–2519 (2007).

    CAS  PubMed  Google Scholar 

  76. 76.

    Chiu, P. S. & Lai, S. C. Matrix metalloproteinase-9 leads to claudin-5 degradation via the NF-κB pathway in BALB/c mice with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis. PLOS ONE 8, e53370 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Mackerras, M. J. & Sandars, D. F. Lifehistory of the rat lung-worm and its migration through the brain of its host. Nature 173, 956–957 (1954).

    CAS  PubMed  Google Scholar 

  78. 78.

    Graeff-Teixeira, C., da Silva, A. C. & Yoshimura, K. Update on eosinophilic meningoencephalitis and its clinical relevance. Clin. Microbiol. Rev. 22, 322–348 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Pittella, J. E. Neurocysticercosis. Brain Pathol. 7, 681–693 (1997).

    CAS  PubMed  Google Scholar 

  80. 80.

    Mishra, P. K. & Teale, J. M. Changes in gene expression of pial vessels of the blood brain barrier during murine neurocysticercosis. PLOS Negl. Trop. Dis. 7, e2099 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Alvarez, J. I. & Teale, J. M. Breakdown of the blood brain barrier and blood-cerebrospinal fluid barrier is associated with differential leukocyte migration in distinct compartments of the CNS during the course of murine NCC. J. Neuroimmunol. 173, 45–55 (2006).

    CAS  PubMed  Google Scholar 

  82. 82.

    Moyano, L. M. et al. High prevalence of asymptomatic neurocysticercosis in an endemic rural community in Peru. PLOS Negl. Trop. Dis. 10, e0005130 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Yadav, R. Y., Ghosh, A., Sharma, K. & Ahmad, S. Atypical presentation of live cysticercus larva in anterior chamber. J. Indian Med. Assoc. 111, 264–265 (2013).

    PubMed  Google Scholar 

  84. 84.

    Bypareddy, R. et al. Mobile subretinal cysticercus imaged by spectral-domain optical coherence tomography with motion tracker. Retin. Cases Brief Rep. (2016).

    Article  Google Scholar 

  85. 85.

    Coureuil, M. et al. Meningococcus hijacks a β2-adrenoceptor/β-arrestin pathway to cross brain microvasculature endothelium. Cell 143, 1149–1160 (2010).

    CAS  PubMed  Google Scholar 

  86. 86.

    Schubert-Unkmeir, A. et al. Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8. PLOS Pathog. 6, e1000874 (2010).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Miner, J. J. & Diamond, M. S. Mechanisms of restriction of viral neuroinvasion at the blood–brain barrier. Curr. Opin. Immunol. 38, 18–23 (2016).

    CAS  PubMed  Google Scholar 

  88. 88.

    Swanson, P. A. 2nd & McGavern, D. B. Viral diseases of the central nervous system. Curr. Opin. Virol. 11, 44–54 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Chapagain, M. L. & Nerurkar, V. R. Human polyomavirus JC (JCV) infection of human B lymphocytes: a possible mechanism for JCV transmigration across the blood-brain barrier. J. Infect. Dis. 202, 184–191 (2010).

    CAS  Google Scholar 

  90. 90.

    Barkhordarian, A. et al. Viral immune surveillance: toward a TH17/TH9 gate to the central nervous system. Bioinformation 11, 47–54 (2015).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Chen, C. J. et al. Infection of pericytes in vitro by Japanese encephalitis virus disrupts the integrity of the endothelial barrier. J. Virol. 88, 1150–1161 (2014).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Elahi, S. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504, 158–162 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011).

    PubMed  Google Scholar 

  94. 94.

    Mantel, P. Y. et al. Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria. Nat. Commun. 7, 12727 (2016).

    CAS  Google Scholar 

  95. 95.

    Swanson, P. A. 2nd et al. CD8+ T cells induce fatal brainstem pathology during cerebral malaria via luminal antigen-specific engagement of brain vasculature. PLOS Pathog. 12, e1006022 (2016).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Sjolinder, H. & Jonsson, A. B. Olfactory nerve — a novel invasion route of Neisseria meningitidis to reach the meninges. PLOS ONE 5, e14034 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Mogk, S. et al. African trypanosomes and brain infection — the unsolved question. Biol. Rev. Camb. Philos. Soc. 92, 1675–1687 (2016).

    PubMed  Google Scholar 

  98. 98.

    Gao, F. et al. Clinical patterns of uveitis in a tertiary center in North China. Ocul. Immunol. Inflamm. 25, S1–S7 (2016).

    PubMed  Google Scholar 

  99. 99.

    Read, R. W., Zhang, J. A., Ishimoto, S. I. & Rao, N. A. Evaluation of the role of human retinal vascular endothelial cells in the pathogenesis of CMV retinitis. Ocular Immunol. Inflamm. 7, 139–146 (1999).

    CAS  Google Scholar 

  100. 100.

    Wolburg, H. et al. Late stage infection in sleeping sickness. PLOS ONE 7, e34304 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Ng, K. Y., Leong, M. K., Liang, H. & Paxinos, G. Melatonin receptors: distribution in mammalian brain and their respective putative functions. Brain Struct. Funct. 222, 2921–2939 (2017).

    CAS  PubMed  Google Scholar 

  102. 102.

    Figarella, K. et al. Prostaglandin-induced programmed cell death in Trypanosoma brucei involves oxidative stress. Cell Death Differ. 13, 1802–1814 (2006).

    CAS  PubMed  Google Scholar 

  103. 103.

    Hovsepian, E. et al. Modulation of inflammatory response and parasitism by 15-deoxy-Δ12,14 prostaglandin J2 in Trypanosoma cruzi-infected cardiomyocytes. Int. J. Parasitol. 41, 553–562 (2011).

    CAS  PubMed  Google Scholar 

  104. 104.

    Rowe, A. M. et al. Herpes keratitis. Prog. Retin. Eye. Res. 32, 88–101 (2013).

    CAS  PubMed  Google Scholar 

  105. 105.

    Vann, V. R. & Atherton, S. S. Neural spread of herpes simplex virus after anterior chamber inoculation. Invest. Ophthalmol. Vis. Sci. 32, 2462–2472 (1991).

    CAS  PubMed  Google Scholar 

  106. 106.

    McBride, P. A. et al. Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J. Virol. 75, 9320–9327 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Shinya, K. et al. Subclinical brain injury caused by H5N1 influenza virus infection. J. Virol. 85, 5202–5207 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Yamada, M. et al. Multiple routes of invasion of wild-type Clade 1 highly pathogenic avian influenza H5N1 virus into the central nervous system (CNS) after intranasal exposure in ferrets. Acta Neuropathol. 124, 505–516 (2012).

    CAS  PubMed  Google Scholar 

  109. 109.

    van Riel, D. et al. Evidence for influenza virus CNS invasion along the olfactory route in an immunocompromised infant. J. Infect. Dis. 210, 419–423 (2014).

    Google Scholar 

  110. 110.

    St John, J. A. et al. Burkholderia pseudomallei penetrates the brain via destruction of the olfactory and trigeminal nerves: implications for the pathogenesis of neurological melioidosis. mBio 5, e00025 (2014).

    Google Scholar 

  111. 111.

    St John, J. A. et al. Burkholderia pseudomallei rapidly infects the brain stem and spinal cord via the trigeminal nerve after intranasal inoculation. Infect. Immun. 84, 2681–2688 (2016).

    Google Scholar 

  112. 112.

    Miner, J. J. et al. Zika virus infection in mice causes panuveitis with shedding of virus in tears. Cell Rep. 16, 3208–3218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Varkey, J. B. et al. Persistence of Ebola virus in ocular fluid during convalescence. N. Engl. J. Med. 372, 2423–2427 (2015). This paper demonstrates that survivors of EBOV infection harboured latent EBOV that could reactivate and cause systemic illness in sites commonly associated with IP, such as the eye.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Orlova, M. & Schurr, E. Human genomics of Mycobacterium tuberculosis infection and disease. Curr. Genet. Med. Rep. 5, 125–131 (2017).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Collins-McMillen, D. & Goodrum, F. D. The loss of binary: pushing the herpesvirus latency paradigm. Curr. Clin. Microbiol. Rep. 4, 124–131 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front. Aging Neurosci. 6, 202 (2014).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    McGavern, D. B. & Kang, S. S. Illuminating viral infections in the nervous system. Nat. Rev. Immunol. 11, 318–329 (2011). This excellent review of the strategies that neurotropic viruses adopt to invade the CNS discusses how viruses establish latent and persistent infections in the CNS and demonstrates how immune surveillance of CNS virus infection can have both beneficial and damaging effects.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Nikkels, A. F. et al. Distribution of varicella-zoster virus DNA and gene products in tissues of a first-trimester varicella-infected fetus. J. Infect. Dis. 191, 540–545 (2005).

    CAS  Google Scholar 

  119. 119.

    Wohlfert, E. A., Blader, I. J. & Wilson, E. H. Brains and brawn: toxoplasma infections of the central nervous system and skeletal muscle. Trends Parasitol. 33, 519–531 (2017).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Nikolich-Zugich, J. Ageing and life-long maintenance of T cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8, 512–522 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Yamaoka, S. et al. Defect of rabies virus phosphoprotein in its interferon-antagonist activity negatively affects viral replication in muscle cells. J. Vet. Med. Sci. 79, 1394–1397 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Razonable, R. R. Rare, unusual, and less common virus infections after organ transplantation. Curr. Opin. Organ. Transplant 16, 580–587 (2011). This paper is a reminder that organ transplants harbour latent pathogens, including rare pathogens such as prions, and, given the high prevalence of pathogens such as CMV, suggests that latent pathogens contribute to graft rejection as well as transmission of infectious agents and indeed may underlie much of the pathology of graft-versus-host disease.

    CAS  PubMed  Google Scholar 

  123. 123.

    Ansari, A. A. Clinical features and pathobiology of Ebolavirus infection. J. Autoimmun. 55, 1–9 (2014).

    PubMed  Google Scholar 

  124. 124.

    Leung, P., Eltahla, A. A., Lloyd, A. R., Bull, R. A. & Luciani, F. Understanding the complex evolution of rapidly mutating viruses with deep sequencing: beyond the analysis of viral diversity. Virus Res. 15, 43–54 (2016).

    Google Scholar 

  125. 125.

    Shao, Q. et al. Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage. Development 143, 4127–4136 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Vasilakis, N. & Weaver, S. C. Flavivirus transmission focusing on Zika. Curr. Opin. Virol. 22, 30–35 (2016).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Major, E. O., Amemiya, K., Tornatore, C. S., Houff, S. A. & Berger, J. R. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin. Microbiol. Rev. 5, 49–73 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Serafini, B. et al. Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B cell activation. J. Neuropathol. Exp. Neurol. 69, 677–693 (2010).

    CAS  PubMed  Google Scholar 

  129. 129.

    Huser, D. et al. High prevalence of infectious adeno-associated virus (AAV) in human peripheral blood mononuclear cells indicative of T lymphocytes as sites of AAV persistence. J. Virol. 91, e02137–16 (2017).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Monaco, M. C., Atwood, W. J., Gravell, M., Tornatore, C. S. & Major, E. O. JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency. J. Virol. 70, 7004–7012 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Haley, M. J., Brough, D., Quintin, J. & Allan, S. M. Microglial priming as trained immunity in the brain. Neuroscience (2017).

    Article  PubMed  Google Scholar 

  132. 132.

    Castellano, P., Prevedel, L. & Eugenin, E. A. HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci. Rep. 7, 12866 (2017).

    Google Scholar 

  133. 133.

    Avalos, C. R. et al. Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. mBio 8, e01186–17 (2017).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Harker, K. S., Jivan, E., McWhorter, F. Y., Liu, W. F. & Lodoen, M. B. Shear forces enhance Toxoplasma gondii tachyzoite motility on vascular endothelium. mBio 5, e01111–13 (2014).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Bayliss, J., Karasoulos, T. & McLean, C. A. Frequency and large T (LT) sequence of JC polyomavirus DNA in oligodendrocytes, astrocytes and granular cells in non-PML brain. Brain Pathol. 22, 329–336 (2012).

    CAS  PubMed  Google Scholar 

  136. 136.

    Churchill, M. & Nath, A. Where does HIV hide? A focus on the central nervous system. Curr. Opin. HIV AIDS 8, 165–169 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Thompson, K. A., Cherry, C. L., Bell, J. E. & McLean, C. A. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am. J. Pathol. 179, 1623–1629 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Hunter, C. A. & Remington, J. S. Immunopathogenesis of toxoplasmic encephalitis. J. Infect. Dis. 170, 1057–1067 (1994).

    CAS  Google Scholar 

  139. 139.

    Miklossy, J. et al. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J. Neuroinflamm. 5, 40 (2008).

    Google Scholar 

  140. 140.

    Bhattacharyya, A. et al. Involvement of the choroid plexus in neurotuberculosis: MR findings in six cases. Neuroradiol. J. 23, 590–595 (2010).

    CAS  PubMed  Google Scholar 

  141. 141.

    Nazari, H., Karakousis, P. C. & Rao, N. A. Replication of Mycobacterium tuberculosis in retinal pigment epithelium. JAMA Ophthalmol. 132, 724–729 (2014).

    PubMed  Google Scholar 

  142. 142.

    Wu, H. S., Kolonoski, P., Chang, Y. Y. & Bermudez, L. E. Invasion of the brain and chronic central nervous system infection after systemic Mycobacterium avium complex infection in mice. Infect. Immun. 68, 2979–2984 (2000).

    CAS  Google Scholar 

  143. 143.

    Lima, C. & Vital, J. P. Olfactory pathways in three patients with cryptococcal meningitis and acquired immune deficiency syndrome. J. Neurol. Sci. 123, 195–199 (1994).

    CAS  PubMed  Google Scholar 

  144. 144.

    Coelho, C., Bocca, A. L. & Casadevall, A. The intracellular life of Cryptococcus neoformans. Annu. Rev. Pathol. 9, 219–238 (2014).

    CAS  PubMed  Google Scholar 

  145. 145.

    Hayes, J. B. et al. Modulation of macrophage inflammatory nuclear factor κB (NF-κB) signaling by intracellular Cryptococcus neoformans. J. Biol. Chem. 291, 15614–15627 (2016).

    CAS  PubMed  Google Scholar 

  146. 146.

    Cavanaugh, S. E., Holmgren, A. M. & Rall, G. F. Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J. Neuroimmunol. 279, 11–19 (2015).

    CAS  PubMed  Google Scholar 

  147. 147.

    Kurapati, S. et al. Role of the JNK pathway in varicella-zoster virus lytic infection and reactivation. J. Virol. 91, e00640–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Skuja, S. et al. Structural and ultrastructural alterations in human olfactory pathways and possible associations with herpesvirus 6 infection. PLOS ONE 12, e0170071 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Akhvlediani, T., Gochitashvili, N. & Tsertsvadze, T. Prion diseases — mysterious persistent infections. Georgian Med. News 146, 38–42 (2007).

    Google Scholar 

  150. 150.

    Liu, Y. et al. Neuronal IFN-beta-induced PI3K/Akt-FoxA1 signalling is essential for generation of FoxA1+Treg cells. Nat. Commun. 8, 14709 (2017).

    Google Scholar 

  151. 151.

    Medana, I. et al. Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J. Immunol. 167, 674–681 (2001).

    CAS  PubMed  Google Scholar 

  152. 152.

    Mykicki, N. et al. Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease. Sci. Transl Med. 8, 362ra146. (2016).

    Google Scholar 

  153. 153.

    Tisato, V., Gonelli, A., Voltan, R., Secchiero, P. & Zauli, G. Clinical perspectives of TRAIL: insights into central nervous system disorders. Cell. Mol. Life Sci. 73, 2017–2027 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Medzhitov, R. & Janeway, C. A. Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).

    CAS  PubMed  Google Scholar 

  155. 155.

    McCarthy, G. M., Bridges, C. R., Blednov, Y. A. & Harris, R. A. CNS cell-type localization and LPS response of TLR signaling pathways. F1000Res 6, 1144 (2017).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Kigerl, K. A., de Rivero Vaccari, J. P., Dietrich, W. D., Popovich, P. G. & Keane, R. W. Pattern recognition receptors and central nervous system repair. Exp. Neurol. 258, 5–16 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Moseman, E. A., Wu, T., de la Torre, J. C., Schwartzberg, P. L. & McGavern, D. B. Type I interferon suppresses virus-specific B cell responses by modulating CD8+ T cell differentiation. Sci. Immunol. 1, eaah3565 (2016).

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Alvarez-Carbonell, D. et al. Toll-like receptor 3 activation selectively reverses HIV latency in microglial cells. Retrovirology 14, 9 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Lobo-Silva, D., Carriche, G. M., Castro, A. G., Roque, S. & Saraiva, M. Balancing the immune response in the brain: IL-10 and its regulation. J. Neuroinflamm. 13, 297 (2016).

    Google Scholar 

  160. 160.

    Lobo-Silva, D., Carriche, G. M., Castro, A. G., Roque, S. & Saraiva, M.Interferon-β regulates the production of IL-10 by Toll-like receptor-activated microglia. Glia 65, 1439–1451 (2017).

    PubMed  Google Scholar 

  161. 161.

    Zauner, L. & Nadal, D. Understanding TLR9 action in Epstein-Barr virus infection. Front. Biosci. 17, 1219–1231 (2012).

    CAS  Google Scholar 

  162. 162.

    Schlaepfer, E., Audige, A., Joller, H. & Speck, R. F. TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J. Immunol. 176, 2888–2895 (2006).

    CAS  PubMed  Google Scholar 

  163. 163.

    Sullivan, W. J. Jr & Jeffers, V. Mechanisms of Toxoplasma gondii persistence and latency. FEMS Microbiol. Rev. 36, 717–733 (2012).

    CAS  PubMed  Google Scholar 

  164. 164.

    Wallace, G. R. & Stanford, M. R. Immunity and Toxoplasma retinochoroiditis. Clin. Exp. Immunol. 153, 309–315 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Suzuki, Y., Orellana, M. A., Schreiber, R. D. & Remington, J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 240, 516–518 (1988).

    CAS  PubMed  Google Scholar 

  166. 166.

    Ochiai, E. et al. CXCL9 is important for recruiting immune T cells into the brain and inducing an accumulation of the T cells to the areas of tachyzoite proliferation to prevent reactivation of chronic cerebral infection with Toxoplasma gondii. Am. J. Pathol. 185, 314–324 (2015).

    CAS  PubMed  Google Scholar 

  167. 167.

    Sugi, T. et al. Toxoplasma gondii cyclic AMP-dependent protein kinase subunit 3 is involved in the switch from tachyzoite to bradyzoite development. mBio 7, e00755–16 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    White, M. W., Radke, J. R. & Radke, J. B. Toxoplasma development - turn the switch on or off? Cell. Microbiol. 16, 466–472 (2014).

    CAS  PubMed  Google Scholar 

  169. 169.

    Rock, R. B., Olin, M., Baker, C. A., Molitor, T. W. & Peterson, P. K. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin. Microbiol. Rev. 21, 243–261 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Gautam, U. S. et al. In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 115, E62–E71 (2018).

    CAS  PubMed  Google Scholar 

  171. 171.

    Lafond, R. E. & Lukehart, S. A. Biological basis for syphilis. Clin. Microbiol. Rev. 19, 29–49 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Amin, D. N. et al. Distinct Toll-like receptor signals regulate cerebral parasite load and interferon alpha/beta and tumor necrosis factor alpha-dependent T cell infiltration in the brains of Trypanosoma brucei-infected mice. J. Infect. Dis. 205, 320–332 (2012).

    CAS  Google Scholar 

  173. 173.

    Goldmann, T., Blank, T. & Prinz, M. Fine-tuning of type I IFN-signaling in microglia—implications for homeostasis, CNS autoimmunity and interferonopathies. Curr. Opin. Neurobiol. 36, 38–42 (2016).

    CAS  PubMed  Google Scholar 

  174. 174.

    Yarovinsky, F. Innate immunity to Toxoplasma gondii infection. Nat. Rev. Immunol. 14, 109–121 (2014).

    CAS  PubMed  Google Scholar 

  175. 175.

    Fox, J. M. & Diamond, M. S. Immune-mediated protection and pathogenesis of chikungunya virus. J. Immunol. 197, 4210–4218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Fros, J. J. et al. Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling. J. Virol. 84, 10877–10887 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Rojas, J. M., Avia, M., Martin, V. & Sevilla, N. IL-10: a multifunctional cytokine in viral infections. J. Immunol. Res. 2017, 6104054 (2017).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Senecal, V. et al. Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: modulation of local immune responses. Glia 64, 553–569 (2016).

    PubMed  Google Scholar 

  179. 179.

    Allen, H. B. Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-β with regard to potential treatment and prevention. J. Alzheimers Dis. 53, 1271–1276 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Fan, C. K., Holland, C. V., Loxton, K. & Barghouth, U. Cerebral toxocariasis: silent progression to neurodegenerative disorders? Clin. Microbiol. Rev. 28, 663–686 (2015).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Itzhaki, R. F. & Tabet, N. Herpes simplex encephalitis and Alzheimer’s disease: is there a link? J. Neurol. Sci. 380, 20–21 (2017).

    PubMed  Google Scholar 

  182. 182.

    Miklossy, J. Bacterial amyloid and DNA are important constituents of senile plaques: further evidence of the spirochetal and biofilm nature of senile plaques. J. Alzheimers Dis. 53, 1459–1473 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Pisa, D., Alonso, R., Rabano, A., Rodal, I. & Carrasco, L. Different brain regions are infected with fungi in Alzheimer’s disease. Sci. Rep. 5, 15015 (2015).

    CAS  Google Scholar 

  184. 184.

    Pisa, D., Alonso, R., Juarranz, A., Rabano, A. & Carrasco, L. Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J. Alzheimers Dis. 43, 613–624 (2015).

    CAS  PubMed  Google Scholar 

  185. 185.

    Kell, D. B. & Pretorius, E. Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Prog. Biophys. Mol. Biol. 123, 16–41 (2017).

    CAS  PubMed  Google Scholar 

  186. 186.

    Miklossy, J. Alzheimer’s disease - a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J. Neuroinflamm. 8, 90 (2011).

    Google Scholar 

  187. 187.

    Bridge, T. P. & Ingraham, L. J. Central nervous system effects of human immunodeficiency virus type 1. Annu. Rev. Med. 41, 159–168 (1990).

    CAS  PubMed  Google Scholar 

  188. 188.

    Andersen, L. L. et al. Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J. Exp. Med. 212, 1371–1379 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Lim, H. K. et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology 83, 1888–1897 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Praet, N. et al. Infection with versus exposure to Taenia solium: what do serological test results tell us? Am. J. Trop. Med. Hyg. 83, 413–415 (2010).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Matzinger, P. & Kamala, T. Tissue-based class control: the other side of tolerance. Nat. Rev. Immunol. 11, 221–230 (2011). In this paper, Matzinger and Kamala offer a self-evident explanation for how the immune response is shaped by the tissue context in which it takes place, an explanation that effectively includes the phenomenon of IP.

    CAS  PubMed  Google Scholar 

  192. 192.

    Hentzen, B. T. & Schreij, G. Patterns of morbidity and mortality in AIDS patients on Pneumocystis carinii prophylaxis who died during hospital admission: a report of 50 diseased patients. Neth. J. Med. 49, 101–105 (1996).

    CAS  PubMed  Google Scholar 

  193. 193.

    Forrester, J. V., Dick, A. D., McMenamin, P., Pearlman, E. & Roberts, F. The Eye - Basic Science in Practice 4th edn. (Elsevier, 2015).

  194. 194.

    Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D. & Ploix, C. C. CNS immune privilege: hiding in plain sight. Immunol. Rev. 213, 48–65 (2006).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Chee, S. P. & Jap, A. Cytomegalovirus anterior uveitis: outcome of treatment. Br. J. Ophthalmol. 94, 1648–1652 (2010).

    PubMed  Google Scholar 

  196. 196.

    Megaw, R. & Agarwal, P. K. Posner-Schlossman syndrome. Survey Ophthalmol. 62, 277–285 (2017).

    Google Scholar 

  197. 197.

    Zambrano, W. et al. Management options for Propionibacterium acnes endophthalmitis. Ophthalmology 96, 1100–1105 (1989).

    CAS  PubMed  Google Scholar 

  198. 198.

    Voigt, V. et al. Cytomegalovirus establishes a latent reservoir and triggers long-lasting inflammation in the eye. PLOS Pathog. 14, e1007040 (2018).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Ortak, H. et al. Age-related changes of aquaporin expression patterns in the postnatal rat retina. Acta Histochem. 115, 382–388 (2013).

    CAS  PubMed  Google Scholar 

  200. 200.

    Lobato-Alvarez, J. A. et al. The apical localization of Na+, K+-ATPase in cultured human retinal pigment epithelial cells depends on expression of the β2 subunit. Front. Physiol. 7, 450 (2016).

    PubMed  PubMed Central  Google Scholar 

  201. 201.

    Rizzolo, L. J. Polarity and the development of the outer blood-retinal barrier. Histol. Histopathol. 12, 1057–1067 (1997).

    CAS  PubMed  Google Scholar 

  202. 202.

    Aspelund, A. et al. The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J. Clin. Invest. 124, 3975–3986 (2014). This article provides compelling evidence on drainage of intraocular fluids through channels in the anterior chamber angle of the eye (Schlemm’s canal), which, for the first time, are described as having lymphatic-like properties.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Wenkel, H., Streilein, J. W. & Young, M. J. Systemic immune deviation in the brain that does not depend on the integrity of the blood–brain barrier. J. Immunol. 164, 5125–5131 (2000).

    CAS  PubMed  Google Scholar 

  204. 204.

    Li, X. Y., D’Orazio, L. T. & Niederkorn, J. Y. Role of Th1 and Th2 cells in anterior chamber-associated immune deviation. Immunology 89, 34–40 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Zhang-Hoover, J. & Stein-Streilein, J. Therapies based on principles of ocular immune privilege. Chem. Immunol. Allergy 92, 317–327 (2007).

    CAS  PubMed  Google Scholar 

  206. 206.

    Stein-Streilein, J. Mechanisms of immune privilege in the posterior eye. Int. Rev. Immunol. 32, 42–56 (2013).

    CAS  PubMed  Google Scholar 

  207. 207.

    Li, X. Y. et al. The induction of splenic suppressor T cells through an immune-privileged site requires an intact sympathetic nervous system. J. Neuroimmunol. 153, 40–49 (2004).

    CAS  PubMed  Google Scholar 

  208. 208.

    Zhang, X., Zhivaki, D. & Lo-Man, R. Unique aspects of the perinatal immune system. Nat. Rev. Immunol. 17, 495–507 (2017).

    CAS  PubMed  Google Scholar 

  209. 209.

    Sekirov, I., Russell, S. L., Antunes, L. C. & Finlay, B. B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010).

    CAS  PubMed  Google Scholar 

  210. 210.

    Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Ben-Zvi, A. et al. Mfsd2a is critical for the formation and function of the blood–brain barrier. Nature 509, 507–511 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Braniste, V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl Med. 6, 263ra158 (2014). This paper makes important initial observations on the effect of the microbiome on BBB function.

    PubMed  PubMed Central  Google Scholar 

  213. 213.

    Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

    PubMed  Google Scholar 

  214. 214.

    Mayerhofer, R. et al. Diverse action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood–brain barrier disruption, and anxiety in mice. Brain Behav. Immun. 60, 174–187 (2017).

    CAS  PubMed  Google Scholar 

  215. 215.

    Arentsen, T. et al. The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior. Mol. Psychiatry 22, 257–266 (2017).

    CAS  PubMed  Google Scholar 

  216. 216.

    Krishnan, S., Fernandez, G. E., Sacks, D. B. & Prasadarao, N. V. IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells. Cell. Microbiol. 14, 1415–1433 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217.

    Stins, M. F., Badger, J. & Sik Kim, K. Bacterial invasion and transcytosis in transfected human brain microvascular endothelial cells. Microb. Pathog. 30, 19–28 (2001).

    CAS  PubMed  Google Scholar 

  218. 218.

    Kim, B. J. et al. Bacterial induction of Snail1 contributes to blood-brain barrier disruption. J. Clin. Invest. 125, 2473–2483 (2015).

    PubMed  PubMed Central  Google Scholar 

  219. 219.

    Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074–5081 (1997).

    CAS  Google Scholar 

  220. 220.

    Attali, C., Durmort, C., Vernet, T. & Di Guilmi, A. M. The interaction of Streptococcus pneumoniae with plasmin mediates transmigration across endothelial and epithelial monolayers by intercellular junction cleavage. Infect. Immun. 76, 5350–5356 (2008).

    CAS  Google Scholar 

  221. 221.

    Ring, A., Weiser, J. N. & Tuomanen, E. I. Pneumococcal trafficking across the blood–brain barrier. Molecular analysis of a novel bidirectional pathway. J. Clin. Invest. 102, 347–360 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    van Ginkel, F. W. et al. Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection. Proc. Natl Acad. Sci. USA 100, 14363–14367 (2003).

    PubMed  Google Scholar 

  223. 223.

    Drevets, D. A. et al. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice. J. Immunol. 172, 4418–4424 (2004).

    CAS  PubMed  Google Scholar 

  224. 224.

    Grundler, T. et al. The surface proteins InlA and InlB are interdependently required for polar basolateral invasion by Listeria monocytogenes in a human model of the blood–cerebrospinal fluid barrier. Microbes Infect. 15, 291–301 (2013).

    PubMed  Google Scholar 

  225. 225.

    Jin, Y., Dons, L., Kristensson, K. & Rottenberg, M. E. Neural route of cerebral Listeria monocytogenes murine infection: role of immune response mechanisms in controlling bacterial neuroinvasion. Infect. Immun. 69, 1093–1100 (2001).

    CAS  Google Scholar 

  226. 226.

    Galdiero, M. et al. Haemophilus influenzae porin contributes to signaling of the inflammatory cascade in rat brain. Infect. Immun. 69, 221–227 (2001).

    CAS  Google Scholar 

  227. 227.

    Be, N. A., Kim, K. S., Bishai, W. R. & Jain, S. K. Pathogenesis of central nervous system tuberculosis. Curr. Mol. Med. 9, 94–99 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228.

    Jain, N. & Walker, W. A. Diet and host-microbial crosstalk in postnatal intestinal immune homeostasis. Nat. Rev. Gastroenterol. Hepatol. 12, 14–25 (2015).

    CAS  PubMed  Google Scholar 

  229. 229.

    Schwerk, C. et al. Polar invasion and translocation of Neisseria meningitidis and Streptococcus suis in a novel human model of the blood–cerebrospinal fluid barrier. PLOS ONE 7, e30069 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Menicucci, A. R. et al. Transcriptome analysis of circulating immune cell subsets highlight the role of monocytes in Zaire Ebola virus Makona pathogenesis. Front. Immunol. 8, 1372 (2017).

    Google Scholar 

  231. 231.

    Smith, J. R. et al. Retinal pigment epithelial cells are a potential reservoir for Ebola virus in the human eye. Transl Vis. Sci. Technol. 6, 12 (2017).

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Dutta, K., Mishra, M. K., Nazmi, A., Kumawat, K. L. & Basu, A. Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection. Immunobiology 215, 884–893 (2010).

    CAS  PubMed  Google Scholar 

  233. 233.

    Yamada, M., Nakamura, K., Yoshii, M., Kaku, Y. & Narita, M. Brain lesions induced by experimental intranasal infection of Japanese encephalitis virus in piglets. J. Comp. Pathol. 141, 156–162 (2009).

    CAS  PubMed  Google Scholar 

  234. 234.

    Brown, A. N., Kent, K. A., Bennett, C. J. & Bernard, K. A. Tissue tropism and neuroinvasion of West Nile virus do not differ for two mouse strains with different survival rates. Virology 368, 422–430 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    Paul, A. M. et al. Osteopontin facilitates West Nile virus neuroinvasion via neutrophil “Trojan horse” transport. Sci. Rep. 7, 4722 (2017).

    Google Scholar 

  236. 236.

    Roe, K. et al. West Nile virus-induced disruption of the blood–brain barrier in mice is characterized by the degradation of the junctional complex proteins and increase in multiple matrix metalloproteinases. J. Gen. Virol. 93, 1193–1203 (2012).

    CAS  Google Scholar 

  237. 237.

    Samuel, M. A., Wang, H., Siddharthan, V., Morrey, J. D. & Diamond, M. S. Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. Proc. Natl Acad. Sci. USA 104, 17140–17145 (2007).

    CAS  PubMed  Google Scholar 

  238. 238.

    Papa, M. P. et al. Zika virus infects, activates, and crosses brain microvascular endothelial cells, without barrier disruption. Front. Microbiol. 8, 2557 (2017).

    Google Scholar 

  239. 239.

    Xu, R. et al. HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9. Brain Res. 1436, 13–19 (2012).

    CAS  PubMed  Google Scholar 

  240. 240.

    Palus, M. et al. Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood–brain barrier integrity. Virology 507, 110–122 (2017).

    CAS  PubMed  Google Scholar 

  241. 241.

    Ruzek, D., Salat, J., Singh, S. K. & Kopecky, J. Breakdown of the blood–brain barrier during tick-borne encephalitis in mice is not dependent on CD8+ T cells. PLOS ONE 6, e20472 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242.

    Menendez, C. M. & Carr, D. J. J. Herpes simplex virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1-specific T cells. J. Neuroinflamm. 14, 124 (2017).

    Google Scholar 

  243. 243.

    Chaves, A. J. et al. Neuroinvasion of the highly pathogenic influenza virus H7N1 is caused by disruption of the blood brain barrier in an avian model. PLOS ONE 9, e115138 (2014).

    PubMed  PubMed Central  Google Scholar 

  244. 244.

    Munster, V. J. et al. Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route. Sci. Rep. 2, 736 (2012).

    Google Scholar 

  245. 245.

    Chai, Q., She, R., Huang, Y. & Fu, Z. F. Expression of neuronal CXCL10 induced by rabies virus infection initiates infiltration of inflammatory cells, production of chemokines and cytokines, and enhancement of blood–brain barrier permeability. J. Virol. 89, 870–876 (2015).

    PubMed  Google Scholar 

  246. 246.

    Lafay, F. et al. Spread of the CVS strain of rabies virus and of the avirulent mutant AvO1 along the olfactory pathways of the mouse after intranasal inoculation. Virology 183, 320–330 (1991).

    CAS  PubMed  Google Scholar 

  247. 247.

    Barragan, A., Brossier, F. & Sibley, L. D. Transepithelial migration of Toxoplasma gondii involves an interaction of intercellular adhesion molecule 1 (ICAM-1) with the parasite adhesin MIC2. Cell. Microbiol. 7, 561–568 (2005).

    CAS  PubMed  Google Scholar 

  248. 248.

    Lachenmaier, S. M., Deli, M. A., Meissner, M. & Liesenfeld, O. Intracellular transport of Toxoplasma gondii through the blood–brain barrier. J. Neuroimmunol. 232, 119–130 (2011).

    CAS  PubMed  Google Scholar 

  249. 249.

    Jarolim, K. L., McCosh, J. K., Howard, M. J. & John, D. T. A light microscopy study of the migration of Naegleria fowleri from the nasal submucosa to the central nervous system during the early stage of primary amebic meningoencephalitis in mice. J. Parasitol. 86, 50–55 (2000).

    CAS  PubMed  Google Scholar 

  250. 250.

    Shibayama, M. et al. Disruption of MDCK cell tight junctions by the free-living amoeba Naegleria fowleri. Microbiology 159, 392–401 (2013).

    CAS  PubMed  Google Scholar 

  251. 251.

    Vu, K., Eigenheer, R. A., Phinney, B. S. & Gelli, A. Cryptococcus neoformans promotes its transmigration into the central nervous system by inducing molecular and cellular changes in brain endothelial cells. Infect. Immun. 81, 3139–3147 (2013).

    CAS  Google Scholar 

  252. 252.

    Jong, A. Y., Stins, M. F., Huang, S. H., Chen, S. H. & Kim, K. S. Traversal of Candida albicans across human blood-brain barrier in vitro. Infect. Immun. 69, 4536–4544 (2001).

    CAS  Google Scholar 

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This Review is based on concepts developed and presented as part of the Ian Constable Lecture, University of Western Australia, 2013 (J.V.F.). J.V.F. acknowledges the generous support of Saving Sight in Grampian under the auspices of I. Fraser and the Development Trust of the University of Aberdeen, Scotland. In addition, J.V.F. thanks the many colleagues, students and associates who have contributed to the numerous discussions and debates surrounding this work, particularly A. Dick and L. Kuffova. P.G.M. acknowledges many past and present honours as well as Ph.D. students and research staff who have studied and worked with the author over the past 35 years, particularly D. Aitken, H. Chinnery and J. Kezic. P.G.M. acknowledges funding from the Australian National Health and Medical Research Council (APP1069979).

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Nature Reviews Neuroscience thanks C. Bergmann, G. Rall and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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J.V.F. conceived and researched data for the article and wrote the Review. P.G.M. and S.J.D. made substantial contributions to discussions of the content and writing of the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to John V. Forrester.

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Describes pathogens that are extremely dangerous, are often lethal and spread rapidly.


Describing fairly non-virulent pathogens, which may occur as commensal organisms and normally do not cause disease, but take advantage of a ‘weakened’ host, as in immunosuppressed patients, and cause life-threatening disease.

Latent infection

A dormant or non-replicative infection that does not elicit a host immune response; a mechanism of long-term microbial survival or persistence within the host.


The non-parenchymal protective coverings of the brain, comprising the dura mater, arachnoid and pia mater.

Uveal tract

The middle covering layer of the eye, comprising the iris, ciliary body and choroid, the last of which is closely juxtaposed to the neural retina.

Ciliary body

The structure connecting the choroid layer of the uveal tract of the eye to the iris anteriorly. Its muscle tissue controls the ability to focus images, whereas its epithelial layers secrete aqueous humour to maintain intraocular pressure.

Delayed-type hypersensitivity

A T cell-mediated response to antigen, also known as type IV hypersensitivity. Pathological delayed-type hypersensitivity reactions present as granulomas, which contain predominantly T cells and macrophages.

Complement-fixing antibody

Antibody that binds to antigen, producing a complex that binds (fixes) surface complement and initiates the complement cascade.

Glia limitans

A thin but highly effective barrier layer formed by the foot processes of astroglial cells, covering the brain and accompanying vessels as they penetrate the CNS parenchyma, where it forms the limit of the neurovascular unit.

Dendritic cells

(DCs). Professional antigen-presenting cells that capture, process and present antigens to T cells.

Oncotic pressure

A measure of the ‘resistance’ of a tissue generated by its content of fluid (interstitial fluid).

Rostral migratory stream

A route along which neuronal precursors originating from the subventricular zone of the brain migrate to the olfactory bulbs.

Cribriform plate

The paired perforated, sieve-like parts of the ethmoid bone either side of the midline that separates the anterior cranial fossa from the nasal cavity.

Apicomplexan parasite

A phylum containing parasites such as Toxoplasma gondii and Plasmodium spp..


Rapidly proliferating, asexual, infectious stage of coccidia such as Toxoplasma gondii.


An infectious life-threatening disease caused by the Gram-negative bacterium Burkholderia pseudomallei, which is found in soil and water. It is endemic in north-east Australia and southern regions of Asia.

Free fatty acid receptor 2

A G protein-coupled cell membrane receptor that binds free fatty acids (FFAs). The four FFA receptors are signalling receptors for FFAs and are involved in many cell physiological processes.

Type IV pili

Thin appendages found on the surface of many bacteria; they are frequently involved in adhesion to host cells, motility and bacterial conjugation.

Viral immune surveillance

A process in which T cells detect and respond to (for example, become activated by) virus. In doing so, T cells generate cytokines, which weaken the integrity of the blood–CNS barrier.

Lamina propria

The loose connective tissue located beneath mucosal epithelia and its supporting basement membrane.

Virchow-Robin space

Also known as perivascular space; small spaces between blood vessels and the pia mater.

Late genes

Genes produced by replicating virus after initial induction of immediate early and early genes.


The slowly replicating, latent form of Toxoplasma gondii that are located within tissue cysts.


A large protein structure formed during cell death by the release of cytochrome c from mitochondria. It acts as a platform for activity of enzymes such as caspases.

Type I interferon response

Cytokine response of infected cells. Its function is to regulate immune activity by, for example, promoting virus clearance or, in the post-viral stage, promoting immunosuppression.

Plasmacytoid DCs

A rare subgroup of dendritic cells (DCs) that constitutively secrete large amounts of interferon-α and have strong antiviral properties.


Spiral-shaped bacteria, including Treponema pallidum.

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Forrester, J.V., McMenamin, P.G. & Dando, S.J. CNS infection and immune privilege. Nat Rev Neurosci 19, 655–671 (2018).

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