Review Article | Published:

CNS infection and immune privilege

Nature Reviews Neurosciencevolume 19pages655671 (2018) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  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).

  2. 2.

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

  3. 3.

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

  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.

  5. 5.

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

  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).

  7. 7.

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

  8. 8.

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

  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).

  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).

  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).

  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).

  13. 13.

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

  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).

  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.

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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.

  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).

  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).

  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).

  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).

  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).

  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).

  36. 36.

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

  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).

  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).

  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).

  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).

  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).

  42. 42.

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

  43. 43.

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

  44. 44.

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

  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).

  46. 46.

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

  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).

  48. 48.

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

  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).

  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.

  51. 51.

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

  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.

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  61. 61.

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

  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).

  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).

  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).

  65. 65.

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

  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).

  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).

  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).

  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).

  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).

  71. 71.

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

  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).

  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).

  74. 74.

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

  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).

  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).

  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).

  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).

  79. 79.

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

  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).

  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).

  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).

  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).

  84. 84.

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

  85. 85.

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

  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).

  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).

  88. 88.

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

  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).

  90. 90.

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

  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).

  92. 92.

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

  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).

  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).

  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).

  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).

  97. 97.

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

  98. 98.

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

  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).

  100. 100.

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

  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).

  102. 102.

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

  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).

  104. 104.

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

  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).

  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).

  107. 107.

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

  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).

  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).

  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).

  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).

  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).

  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.

  114. 114.

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

  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).

  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).

  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.

  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).

  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).

  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).

  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).

  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.

  123. 123.

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

  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).

  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).

  126. 126.

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

  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).

  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).

  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).

  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).

  131. 131.

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

  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).

  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).

  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).

  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).

  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).

  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).

  138. 138.

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

  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).

  140. 140.

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

  141. 141.

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

  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).

  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).

  144. 144.

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

  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).

  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).

  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).

  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).

  149. 149.

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

  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).

  151. 151.

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

  152. 152.

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

  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).

  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).

  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).

  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).

  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).

  158. 158.

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

  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).

  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).

  161. 161.

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

  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).

  163. 163.

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

  164. 164.

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

  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).

  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).

  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).

  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).

  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).

  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).

  171. 171.

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

  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).

  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).

  174. 174.

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

  175. 175.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  188. 188.

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

  189. 189.

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

  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).

  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.

  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).

  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).

  195. 195.

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

  196. 196.

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

  197. 197.

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

  198. 198.

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

  199. 199.

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

  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).

  201. 201.

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

  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.

  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).

  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).

  205. 205.

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

  206. 206.

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

  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).

  208. 208.

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

  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).

  210. 210.

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

  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).

  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.

  213. 213.

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

  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).

  215. 215.

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

  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).

  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).

  218. 218.

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

  219. 219.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  235. 235.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  250. 250.

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

  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).

  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).

Download references


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).

Reviewer information

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

Author information


  1. Division of Applied Medicine, Section of Immunology and Infection, Institute of Medical Sciences, University of Aberdeen, Scotland, UK

    • John V. Forrester
  2. Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, Crawley, Western Australia, Australia

    • John V. Forrester
  3. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia

    • John V. Forrester
  4. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia

    • Paul G. McMenamin
    •  & Samantha J. Dando


  1. Search for John V. Forrester in:

  2. Search for Paul G. McMenamin in:

  3. Search for Samantha J. Dando in:


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.

Competing interests

The authors declare no conflicts of interest.

Corresponding author

Correspondence to John V. Forrester.

Supplementary information



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.

About this article

Publication history