Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.
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Aliberti, J. Host persistence: exploitation of anti-inflammatory pathways by Toxoplasma gondii. Nat. Rev. Immunol. 5, 162–170 (2005).
Ronca, S.E., Dineley, K.T. & Paessler, S. Neurological sequelae resulting from encephalitic alphavirus infection. Front. Microbiol. 7, 959 (2016).
Barichello, T. et al. Interleukin-1β receptor antagonism prevents cognitive impairment following experimental bacterial meningitis. Curr. Neurovasc. Res. 12, 253–261 (2015).
Chandran, A., Herbert, H., Misurski, D. & Santosham, M. Long-term sequelae of childhood bacterial meningitis: an underappreciated problem. Pediatr. Infect. Dis. J. 30, 3–6 (2011).
Harden, L.M., Kent, S., Pittman, Q.J. & Roth, J. Fever and sickness behavior: friend or foe? Brain Behav. Immun. 50, 322–333 (2015).
Lauritsen, A. & Oberg, B. Adjunctive corticosteroid therapy in bacterial meningitis. Scand. J. Infect. Dis. 27, 431–434 (1995).
Bradshaw, M.J. & Venkatesan, A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics 13, 493–508 (2016).
Clarke, P. et al. Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response. J. Virol. 88, 1080–1089 (2014).
Gupta, K., Banerjee, A., Saggar, K., Ahluwalia, A. & Saggar, K. A prospective study of magnetic resonance imaging patterns of central nervous system infections in pediatric age group and young adults and their clinico-biochemical correlation. J. Pediatr. Neurosci. 11, 46–51 (2016).
Ali, M., Safriel, Y., Sohi, J., Llave, A. & Weathers, S. West Nile virus infection: MR imaging findings in the nervous system. AJNR Am. J. Neuroradiol. 26, 289–297 (2005).
Szretter, K.J. et al. 2′-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo. PLoS Pathog. 8, e1002698 (2012).
Vasek, M.J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).
Leypoldt, F. et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology 81, 1637–1639 (2013).
Kashyap, R.S. et al. Changes in cerebrospinal fluid cytokine expression in tuberculous meningitis patients with treatment. Neuroimmunomodulation 17, 333–339 (2010).
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).
Williams, J.L., Holman, D.W. & Klein, R.S. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers. Front. Cell. Neurosci. 8, 154 (2014).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Iliff, J.J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid-β. Sci. Transl. Med. 4, 147ra111 (2012).
Detje, C.N. et al. Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon-β producers that protect from lethal encephalitis. J. Virol. 89, 2731–2738 (2015).
Malone, K.E., Stohlman, S.A., Ramakrishna, C., Macklin, W. & Bergmann, C.C. Induction of class I antigen processing components in oligodendroglia and microglia during viral encephalomyelitis. Glia 56, 426–435 (2008).
Engelhardt, B. et al. Nat. Immunol. 18, 123–131 (2017).
Schwerk, C., Tenenbaum, T., Kim, K.S. & Schroten, H. The choroid plexus-a multi-role player during infectious diseases of the CNS. Front. Cell. Neurosci. 9, 80 (2015).
Steinemann, A., Galm, I., Chip, S., Nitsch, C. & Maly, I.P. Claudin-1, -2 and -3 are selectively expressed in the epithelia of the choroid plexus of the mouse from early development and into adulthood while claudin-5 is restricted to endothelial cells. Front. Neuroanat. 10, 16 (2016).
Oda, Y. & Nakanishi, I. Ultrastructure of the caudal portion of the fourth ventricular roof in the mouse. J. Comp. Neurol. 256, 299–307 (1987).
Mildner, A. et al. Ly-6G+CCR2− myeloid cells rather than Ly-6ChighCCR2+ monocytes are required for the control of bacterial infection in the central nervous system. J. Immunol. 181, 2713–2722 (2008).
Robinson, K., Taraktsoglou, M., Rowe, K.S., Wooldridge, K.G. & Ala'Aldeen, D.A. Secreted proteins from Neisseria meningitidis mediate differential human gene expression and immune activation. Cell. Microbiol. 6, 927–938 (2004).
Banerjee, A. et al. Activation of brain endothelium by pneumococcal neuraminidase NanA promotes bacterial internalization. Cell. Microbiol. 12, 1576–1588 (2010).
Ernst, J.D., Hartiala, K.T., Goldstein, I.M. & Sande, M.A. Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis. Infect. Immun. 46, 81–86 (1984).
Flierl, M.A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007).
Aydin, N. et al. An experimental study of the neurophysical mechanisms of photophobia induced by subarachnoid hemorrhage. Neurosci. Lett. 630, 93–100 (2016).
Quintana, E. et al. DNGR-1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia 63, 2231–2248 (2015).
Durrant, D.M., Daniels, B.P. & Klein, R.S. IL-1R1 signaling regulates CXCL12-mediated T cell localization and fate within the central nervous system during West Nile Virus encephalitis. J. Immunol. 193, 4095–4106 (2014).
Clarkson, B.D. et al. CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J. Immunol. 194, 531–541 (2015).
Hikita, N. et al. Relationship between severity of aseptic meningitis and cerebrospinal fluid cytokine levels. Osaka City Med. J. 61, 63–71 (2015).
Jarvis, J.N. et al. Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis. PLoS Pathog. 11, e1004754 (2015).
Netea, M.G. et al. Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon-γ therapy. Clin. Infect. Dis. 39, e83–e87 (2004).
Schläger, C. et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530, 349–353 (2016).
Gadani, S.P., Cronk, J.C., Norris, G.T. & Kipnis, J. IL-4 in the brain: a cytokine to remember. J. Immunol. 189, 4213–4219 (2012).
Schmidt, A.K. et al. Adjuvant granulocyte colony-stimulating factor therapy results in improved spatial learning and stimulates hippocampal neurogenesis in a mouse model of pneumococcal meningitis. J. Neuropathol. Exp. Neurol. 74, 85–94 (2015).
Wippel, C. et al. Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage. PLoS Pathog. 9, e1003380 (2013).
Kreutzfeldt, M. et al. Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. J. Exp. Med. 210, 2087–2103 (2013).
Daneman, R. & Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).
Kim, B.J. et al. Bacterial induction of Snail1 contributes to blood-brain barrier disruption. J. Clin. Invest. 125, 2473–2483 (2015).
Daniels, B.P. et al. Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals. MBio 5, e01476–e14 (2014).
Lazear, H.M. et al. Interferon-l restricts West Nile virus neuroinvasion by tightening the blood-brain barrier. Sci. Transl. Med. 7, 284ra59 (2015).
Bhattacharyya, S. et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14, 136–147 (2013).
Miner, J.J. et al. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nat. Med. 21, 1464–1472 (2015).
Terrando, N. et al. Resolving postoperative neuroinflammation and cognitive decline. Ann. Neurol. 70, 986–995 (2011).
Espinosa-Oliva, A.M. et al. Role of dopamine in the recruitment of immune cells to the nigro-striatal dopaminergic structures. Neurotoxicology 41, 89–101 (2014).
Wen, J. et al. TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice. J. Autoimmun. 60, 40–50 (2015).
Blank, T. et al. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity 44, 901–912 (2016).
Nair, S. & Diamond, M.S. Innate immune interactions within the central nervous system modulate pathogenesis of viral infections. Curr. Opin. Immunol. 36, 47–53 (2015).
Nave, K.A. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010).
Eroglu, C. & Barres, B.A. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).
Schitine, C., Nogaroli, L., Costa, M.R. & Hedin-Pereira, C. Astrocyte heterogeneity in the brain: from development to disease. Front. Cell. Neurosci. 9, 76 (2015).
Bardehle, S. et al. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat. Neurosci. 16, 580–586 (2013).
Kipp, M. et al. Brain-region-specific astroglial responses in vitro after LPS exposure. J. Mol. Neurosci. 35, 235–243 (2008).
Morga, E., Faber, C. & Heuschling, P. Cultured astrocytes express regional heterogeneity of the immunoreactive phenotype under basal conditions and after γ-IFN induction. J. Neuroimmunol. 87, 179–184 (1998).
McKimmie, C.S. & Graham, G.J. Astrocytes modulate the chemokine network in a pathogen-specific manner. Biochem. Biophys. Res. Commun. 394, 1006–1011 (2010).
Vesce, S., Rossi, D., Brambilla, L. & Volterra, A. Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. Int. Rev. Neurobiol. 82, 57–71 (2007).
Rossi, D. & Volterra, A. Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res. Bull. 80, 224–232 (2009).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
De Lucia, C. et al. Microglia regulate hippocampal neurogenesis during chronic neurodegeneration. Brain Behav. Immun. 55, 179–190 (2016).
Djukic, M. et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129, 2394–2403 (2006).
Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).
Michell-Robinson, M.A. et al. Roles of microglia in brain development, tissue maintenance and repair. Brain 138, 1138–1159 (2015).
Lai, A.Y., Dhami, K.S., Dibal, C.D. & Todd, K.G. Neonatal rat microglia derived from different brain regions have distinct activation responses. Neuron Glia Biol. 7, 5–16 (2011).
Carter, J.A., Neville, B.G. & Newton, C.R. Neuro-cognitive impairment following acquired central nervous system infections in childhood: a systematic review. Brain Res. Brain Res. Rev. 43, 57–69 (2003).
Lehnardt, S. et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4–dependent pathway. Proc. Natl. Acad. Sci. USA 100, 8514–8519 (2003).
Scheld, W.M., Koedel, U., Nathan, B. & Pfister, H.W. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J. Infect. Dis. 186 (suppl. 2), S225–S233 (2002).
Grindborg, Ö., Naucler, P., Sjölin, J. & Glimåker, M. Adult bacterial meningitis—a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians. Clin. Microbiol. Infect. 21, 560–566 (2015).
Polfliet, M.M. et al. Meningeal and perivascular macrophages of the central nervous system play a protective role during bacterial meningitis. J. Immunol. 167, 4644–4650 (2001).
Gerber, J. & Nau, R. Mechanisms of injury in bacterial meningitis. Curr. Opin. Neurol. 23, 312–318 (2010).
Braun, J.S. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5, 298–302 (1999).
Geldhoff, M. et al. Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis. BMC Infect. Dis. 13, 358 (2013).
Aurangzeb, S., Badshah, M. & Khan, R. S. Chest radiographic findings in neurotuberculosis without pulmonary signs and symptoms. J. Coll. Physici. 18, 27–30 (2008).
Cherian, A. & Thomas, S.V. Central nervous system tuberculosis. Afr. Health Sci. 11, 116–127 (2011).
Pyrgos, V., Seitz, A.E., Steiner, C.A., Prevots, D.R. & Williamson, P.R. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS One 8, e56269 (2013).
Lu, C.H. et al. Assessing the chronic neuropsychologic sequelae of human immunodeficiency virus-negative cryptococcal meningitis by using diffusion tensor imaging. Am. J. Neuroradiol. 32, 1333–1339 (2011).
Hoffmann, M., Muniz, J., Carroll, E. & De Villasante, J. Cryptococcal meningitis misdiagnosed as Alzheimer's disease: complete neurological and cognitive recovery with treatment. J. Alzheimers Dis. 16, 517–520 (2009).
Bratton, E.W. et al. Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS One 7, e43582 (2012).
Garg, R.K. Tuberculosis of the central nervous system. Postgrad. Med. J. 75, 133–140 (1999).
Pelc, S. & De Maertelaere, E. CSF cells in tuberculous meningitis. Humoral and cellular immune response. J. Neurol. Sci. 49, 223–228 (1981).
Park, K.H. et al. Kinetics of T-cell-based assays on cerebrospinal fluid and peripheral blood mononuclear cells in patients with tuberculous meningitis. Korean J. Intern. Med. 29, 793–799 (2014).
Jarvis, J.N. et al. The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis. J. Infect. Dis. 207, 1817–1828 (2013).
Panackal, A.A. et al. Paradoxical immune responses in non-HIV cryptococcal meningitis. PLoS Pathog. 11, e1004884 (2015).
Browne, T.C. et al. IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J. Immunol. 190, 2241–2251 (2013).
Papageorgiou, I.E. et al. TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ. Proc. Natl. Acad. Sci. USA 113, 212–217 (2016).
Bloomfield, P.S. et al. Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11C]PBR28 PET brain imaging study. Am. J. Psychiatry 173, 44–52 (2016).
Mettenleiter, T.C. Breaching the barrier—the nuclear envelope in virus infection. J. Mol. Biol. 428, 1949–1961 (2016).
Granerod, J. et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect. Dis. 10, 835–844 (2010).
Salimi, H., Cain, M.D. & Klein, R.S. Encephalitic arboviruses: emergence, clinical presentation, and neuropathogenesis. Neurotherapeutics 13, 514–534 (2016).
Kramer, L.D., Styer, L.M. & Ebel, G.D. A global perspective on the epidemiology of West Nile virus. Annu. Rev. Entomol. 53, 61–81 (2008).
Altfeld, M. & Gale, M. Jr. Innate immunity against HIV-1 infection. Nat. Immunol. 16, 554–562 (2015).
Armangue, T. et al. Autoimmune post-herpes simplex encephalitis of adults and teenagers. Neurology 85, 1736–1743 (2015).
John, C.C. et al. Global research priorities for infections that affect the nervous system. Nature 527, S178–S186 (2015).
Stahl, J.P., Mailles, A., De Broucker, T., & Steering Committee and Investigators Group. Herpes simplex encephalitis and management of acyclovir in encephalitis patients in France. Epidemiol. Infect. 140, 372–381 (2012).
Garcia, M.N. et al. Evaluation of prolonged fatigue post-West Nile virus infection and association of fatigue with elevated antiviral and proinflammatory cytokines. Viral Immunol. 27, 327–333 (2014).
Sadek, J.R. et al. Persistent neuropsychological impairment associated with West Nile virus infection. J. Clin. Exp. Neuropsychol. 32, 81–87 (2010).
Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).
Chung, W.S., Welsh, C.A., Barres, B.A. & Stevens, B. Do glia drive synaptic and cognitive impairment in disease? Nat. Neurosci. 18, 1539–1545 (2015).
Mehlhop, E. & Diamond, M.S. Protective immune responses against West Nile virus are primed by distinct complement activation pathways. J. Exp. Med. 203, 1371–1381 (2006).
Schafer, D.P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Tremblay, M.E., Lowery, R.L. & Majewska, A.K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Mucke, L. et al. High-level neuronal expression of Aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).
Woollacott, I.O. & Rohrer, J.D. The clinical spectrum of sporadic and familial forms of frontotemporal dementia. J. Neurochem. 138 (suppl. 1), 6–31 (2016).
Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).
Sköldenberg, B. et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet 2, 707–711 (1984).
Sili, U., Kaya, A., Mert, A. & H.S.V.E.S. Group. Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. J. Clin. Virol. 60, 112–118 (2014).
De Tiège, X. et al. Herpes simplex encephalitis relapses in children: differentiation of two neurologic entities. Neurology 61, 241–243 (2003).
Leypoldt, F., Armangue, T. & Dalmau, J. Autoimmune encephalopathies. Ann. NY Acad. Sci. 1338, 94–114 (2015).
Hughes, E.G. et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30, 5866–5875 (2010).
Planagumà, J. et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94–109 (2015).
Mikasova, L. et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 135, 1606–1621 (2012).
Guo, M. et al. A Systematic meta-analysis of Toxoplasma gondii prevalence in food animals in the united states. Foodborne Pathog. Dis. 13, 109–118 (2016).
Ueno, N. & Lodoen, M.B. From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system. Curr. Opin. Microbiol. 26, 53–59 (2015).
White, M.W., Radke, J.R. & Radke, J.B. Toxoplasma development —turn the switch on or off? Cell. Microbiol. 16, 466–472 (2014).
Flegr, J., Lenochová, P., Hodný, Z. & Vondrová, M. Fatal attraction phenomenon in humans: cat odour attractiveness increased for toxoplasma-infected men while decreased for infected women. PLoS Negl. Trop. Dis. 5, e1389 (2011).
Vyas, A., Kim, S.K., Giacomini, N., Boothroyd, J.C. & Sapolsky, R.M. Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc. Natl. Acad. Sci. USA 104, 6442–6447 (2007).
Poirotte, C. et al. Morbid attraction to leopard urine in Toxoplasma-infected chimpanzees. Curr. Biol. 26, R98–R99 (2016).
Blanchard, N., Dunay, I.R. & Schlüter, D. Persistence of Toxoplasma gondii in the central nervous system: a fine-tuned balance between the parasite, the brain and the immune system. Parasite Immunol. 37, 150–158 (2015).
Landrith, T.A., Harris, T.H. & Wilson, E.H. Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain. Semin. Immunopathol. 37, 261–270 (2015).
Cabral, C.M. et al. Neurons are the primary target cell for the brain-tropic intracellular parasite Toxoplasma gondii. PLoS Pathog. 12, e1005447 (2016).
David, C.N. et al. GLT-1-dependent disruption of CNS glutamate homeostasis and neuronal function by the protozoan parasite Toxoplasma gondii. PLoS Pathog. 12, e1005643 (2016).
Parlog, A., Schlüter, D. & Dunay, I.R. Toxoplasma gondii-induced neuronal alterations. Parasite Immunol. 37, 159–170 (2015).
Ingram, W.M., Goodrich, L.M., Robey, E.A. & Eisen, M.B. Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. PLoS One 8, e75246 (2013).
Mahmoudvand, H. et al. Toxoplasma gondii infection promotes neuroinflammation through cytokine networks and induced hyperalgesia in BALB/c mice. Inflammation 39, 405–412 (2016).
Riazi, K. et al. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J. Neurosci. 35, 4942–4952 (2015).
Wu, M.D., Montgomery, S.L., Rivera-Escalera, F., Olschowka, J.A. & O'Banion, M.K. Sustained IL-1β expression impairs adult hippocampal neurogenesis independent of IL-1 signaling in nestin+ neural precursor cells. Brain Behav. Immun. 32, 9–18 (2013).
del Rey, A., Balschun, D., Wetzel, W., Randolf, A. & Besedovsky, H.O. A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain Behav. Immun. 33, 15–23 (2013).
Eells, J.B., Wilcots, J., Sisk, S. & Guo-Ross, S.X. NR4A gene expression is dynamically regulated in the ventral tegmental area dopamine neurons and is related to expression of dopamine neurotransmission genes. J. Mol. Neurosci. 46, 545–553 (2012).
Grimes, D.A. et al. Translated mutation in the Nurr1 gene as a cause for Parkinson's disease. Mov. Disord. 21, 906–909 (2006).
Wei, Y.M., Du, Y.L., Nie, Y.Q., Li, Y.Y. & Wan, Y.J. Nur-related receptor 1 gene polymorphisms and alcohol dependence in Mexican Americans. World J. Gastroenterol. 18, 5276–5282 (2012).
Lallier, S.W., Graf, A.E., Waidyarante, G.R. & Rogers, L.K. Nurr1 expression is modified by inflammation in microglia. Neuroreport 27, 1120–1127 (2016).
Eells, J.B. et al. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity. PLoS One 10, e0119280 (2015).
Hamdani, N. et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J. Affect. Disord. 179, 161–166 (2015).
Ejlerskov, P. et al. Lack of neuronal IFN-β-IFNAR causes Lewy body- and Parkinson's disease-like dementia. Cell 163, 324–339 (2015).
Filiano, A.J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).
Derecki, N.C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).
Jones, L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One 5, e13950 (2010).
Kumar, D.K. et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci. Transl. Med. 8, 340ra72 (2016).
Beatman, E.L. et al. Alpha-synuclein expression restricts RNA viral infections in the brain. J. Virol. 90, 2767–2782 (2015).
Stojakovic, A. et al. Role of the IL-1 pathway in dopaminergic neurodegeneration and decreased voluntary movement. Mol. Neurobiol. http://dx.doi.org/10.1007/s12035-016-9988-x (2016).
Prieto, G.A. et al. Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus. Proc. Natl. Acad. Sci. USA 112, E5078–E5087 (2015).
Cutando, L. et al. Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. J. Clin. Invest. 123, 2816–2831 (2013).
Prajapati, P. et al. TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells. Biochim. Biophys. Acta 1852, 451–461 (2015).
Wu, Y. et al. Upregulation of tumor necrosis factor-α in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model. Biochem. Biophys. Res. Commun. 449, 502–507 (2014).
Pettigrew, L.C., Kryscio, R.J. & Norris, C.M. The TNFα-transgenic rat: hippocampal synaptic integrity, cognition, function, and post-ischemic cell loss. PLoS One 11, e0154721 (2016).
Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).
Wall, A.M., Mukandala, G., Greig, N.H. & O'Connor, J.J. Tumor necrosis factor-α potentiates long-term potentiation in the rat dentate gyrus after acute hypoxia. J. Neurosci. Res. 93, 815–829 (2015).
Chen, Z. & Palmer, T.D. Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis. Brain Behav. Immun. 30, 45–53 (2013).
Habbas, S. et al. Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741 (2015).
Chien, C.H., Lee, M.J., Liou, H.C., Liou, H.H. & Fu, W.M. Microglia-derived cytokines/chemokines are involved in the enhancement of LPS-induced loss of nigrostriatal dopaminergic neurons in DJ-1 knockout mice. PLoS One 11, e0151569 (2016).
Vlkolinský, R., Siggins, G.R., Campbell, I.L. & Krucker, T. Acute exposure to CXC chemokine ligand 10, but not its chronic astroglial production, alters synaptic plasticity in mouse hippocampal slices. J. Neuroimmunol. 150, 37–47 (2004).
Li, L., Walker, T.L., Zhang, Y., Mackay, E.W. & Bartlett, P.F. Endogenous interferon-γ directly regulates neural precursors in the noninflammatory brain. J. Neurosci. 30, 9038–9050 (2010).
Corbin, J.G. et al. Targeted CNS expression of interferon-γ in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol. Cell. Neurosci. 7, 354–370 (1996).
Hoyo-Becerra, C., Schlaak, J.F. & Hermann, D.M. Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation. Brain Behav. Immun. 42, 222–231 (2014).
Zheng, L.S. et al. Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. Stem Cell Reports. 3, 73–84 (2014).
Yang, C.S. et al. Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia. J. Neuroinflammation 4, 27 (2007).
Koedel, U. et al. Experimental pneumococcal meningitis: cerebrovascular alterations, brain edema, and meningeal inflammation are linked to the production of nitric oxide. Ann. Neurol. 37, 313–323 (1995).
Winkler, F., Koedel, U., Kastenbauer, S. & Pfister, H.W. Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood-brain barrier breakdown. J. Infect. Dis. 183, 1749–1759 (2001).
Liu, X., Chauhan, V.S., Young, A.B. & Marriott, I. NOD2 mediates inflammatory responses of primary murine glia to Streptococcus pneumoniae. Glia 58, 839–847 (2010).
Sokolova, O. et al. Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release. Cell. Microbiol. 6, 1153–1166 (2004).
Schubert-Unkmeir, A., Sokolova, O., Panzner, U., Eigenthaler, M. & Frosch, M. Gene expression pattern in human brain endothelial cells in response to Neisseria meningitidis. Infect. Immun. 75, 899–914 (2007).
Steinmann, U. et al. Transmigration of polymorphnuclear neutrophils and monocytes through the human blood-cerebrospinal fluid barrier after bacterial infection in vitro. J. Neuroinflammation 10, 31 (2013).
Cooley, I.D., Chauhan, V.S., Donneyz, M.A. & Marriott, I. Astrocytes produce IL-19 in response to bacterial challenge and are sensitive to the immunosuppressive effects of this IL-10 family member. Glia 62, 818–828 (2014).
Waage, A. et al. Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J. Exp. Med. 170, 1859–1867 (1989).
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).
Lee, S.C., Dickson, D.W., Brosnan, C.F. & Casadevall, A. Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism. J. Exp. Med. 180, 365–369 (1994).
Liang, C.C. et al. Human endothelial cell activation and apoptosis induced by enterovirus 71 infection. J. Med. Virol. 74, 597–603 (2004).
Schneider, H. et al. Chemotaxis of T-cells after infection of human choroid plexus papilloma cells with Echovirus 30 in an in vitro model of the blood-cerebrospinal fluid barrier. Virus Res. 170, 66–74 (2012).
Wang, C. et al. Intrinsic apoptosis and proinflammatory cytokines regulated in human astrocytes infected with enterovirus 71. J. Gen. Virol. 96, 3010–3022 (2015).
Reinert, L.S. et al. TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J. Clin. Invest. 122, 1368–1376 (2012).
Liu, Z. et al. HSV-1 activates NF-kB in mouse astrocytes and increases TNF-α and IL-6 expression via Toll-like receptor 3. Neurol. Res. 35, 755–762 (2013).
Fitting, S. et al. Regional heterogeneity and diversity in cytokine and chemokine production by astroglia: differential responses to HIV-1 Tat, gp120, and morphine revealed by multiplex analysis. J. Proteome Res. 9, 1795–1804 (2010).
Wacher, C. et al. Coordinated regulation and widespread cellular expression of interferon-stimulated genes (ISG) ISG-49, ISG-54, and ISG-56 in the central nervous system after infection with distinct viruses. J. Virol. 81, 860–871 (2007).
Cho, H. et al. Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat. Med. 19, 458–464 (2013).
We thank J. Williams for critical reading of the manuscript. Funding for this research was provided by the US National Institutes of Health grants T32 HL007317 (N.H.), R01 NS052632, P01 NS059560, R01 AI126909, R21AI114549 and U19 AI083019 (R.S.K.) and a grant from the National Multiple Sclerosis society (R.S.K.).
The authors declare no competing financial interests.
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Klein, R., Garber, C. & Howard, N. Infectious immunity in the central nervous system and brain function. Nat Immunol 18, 132–141 (2017). https://doi.org/10.1038/ni.3656
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