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⇱ Coronavirus infection of the central nervous system: host–virus stand-off | Nature Reviews Microbiology

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Key Points

  • Coronaviruses infect humans, rodents and several agriculturally important animals.

  • Mouse hepatitis virus (MHV) causes acute infections of the murine liver and lungs and persistent infections of the gastrointestinal tract and central nervous system (CNS).

  • Interactions of immune effectors and cells of the CNS can be studied using a non-lethal gliatropic strain of MHV. This model sheds light on the interplay of cytokines, chemokines and innate and adaptive immune effectors during acute infection, as well as their role in regulating coronavirus persistence.

  • This review summarizes data that show how distinct phases of CNS infection are associated with the induction of innate danger signals, altered patterns of inflammatory cells and expression of antiviral effector functions. This leads to a state of virus–host coexistence that is beneficial to the survival of both.

  • During acute infection, the principal antiviral effectors are virus-specific T cells, which use distinct mechanisms to control virus replication in a CNS-cell-type specific manner. Control of viral replication in CNS-resident macrophages (microglia) and astrocytes is dependent on CD8+ T-cell perforin-mediated cytolysis. By contrast, control of replication in oligodendrocytes requires secretion of the soluble mediator, interferon-Ξ³.

  • Control of virus replication is accompanied by downregulation of CD8+ T-cell cytolytic function and recruitment of virus-specific antibody-secreting cells into the CNS. Maintenance of local secretion of neutralizing antibody is crucial in preventing the re-emergence of infectious virus, indicating that virus persists in a replication-competent form.

  • In the MHV model, the limitation of prolonged cytolytic activity sustains CNS function, while soluble mediators control, but cannot eradicate, persistent infection.

Abstract

Several viruses infect the mammalian central nervous system (CNS), some with devastating consequences, others resulting in chronic or persistent infections associated with little or no overt pathology. Coronavirus infection of the murine CNS illustrates the contributions of both the innate immune response and specific host effector mechanisms that control virus replication in distinct CNS cell types. Despite T-cell-mediated control of acute virus infection, host regulatory mechanisms, probably designed to protect CNS integrity, contribute to the failure to eliminate virus. Distinct from cytolytic effector mechanisms expressed during acute infection, non-lytic humoral immunity prevails in suppressing infectious virus during persistence.

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Figure 1: Summary of mouse hepatitis virus (MHV) replication.
The alternative text for this image may have been generated using AI.
Figure 2: Kinetics of viral spread and central nervous system (CNS) tropism.
The alternative text for this image may have been generated using AI.
Figure 3: Host responses in the central nervous system (CNS) associated with neurotropic coronavirus replication.
The alternative text for this image may have been generated using AI.
Figure 4: Kinetics of the cellular and humoral inflammatory response to neurotropic coronavirus infection.
The alternative text for this image may have been generated using AI.
Figure 5: Distinct immune effector mechanisms control acute and persistent infection.
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References

  1. Fabry, Z., Raine, C. S. & Hart, M. N. Nervous tissue as an immune compartment: the dialect of the immune response in the CNS. Immunol. Today 15, 218–224 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Hickey, W. F. Basic principles of immunological surveillance of the normal central nervous system. Glia 36, 118–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Aloisi, F., Ria, F. & Adorini, L. Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol. Today 21, 141–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Johnson, M. D., Gold, L. I. & Moses, H. L. Evidence for transforming growth factor-Ξ² expression in human leptomeningeal cells and transforming growth factor-Ξ²-like activity in human cerebrospinal fluid. Lab. Invest. 67, 360–368 (1992).

    CAS  PubMed  Google Scholar 

  5. Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Neumann, H., Misgeld, T., Matsumuro, K. & Wekerle, H. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc. Natl Acad. Sci. USA 95, 5779–5784 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dorries, R. The role of T-cell-mediated mechanisms in virus infections of the nervous system. Curr. Top. Microbiol. Immunol. 253, 219–245 (2001).

    CAS  PubMed  Google Scholar 

  8. Ransohoff, R. M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nature Rev. Immunol. 3, 569–581 (2003).

    Article  CAS  Google Scholar 

  9. Griffin, D. E. Immune responses to RNA-virus infections of the CNS. Nature Rev. Immunol. 3, 493–502 (2003).

    Article  CAS  Google Scholar 

  10. Belkaid, Y. & Rouse, B. T. Natural regulatory T cells in infectious disease. Nature Immunol. 6, 353–360 (2005).

    Article  CAS  Google Scholar 

  11. Jiang, H. & Chess, L. An integrated view of suppressor T cell subsets in immunoregulation. J. Clin. Invest. 114, 1198–1208 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lipton, H. & Gilden, D. Viral diseases of the central nervous system: persistent infections. In Viral Pathogenesis (ed. Nathanson, N.) 855–870 (Lippincott–Rave, Philadelphia, 1997).

    Google Scholar 

  13. Rall, G. & Oldstone, M. Viral persistence in the central nervous system. In In Defense Of The Brain: Current Concepts In The Immunopathogenesis And Clinical Aspects Of CNS Infection 273–289 (Blackwell Science, Malden, 1997).

    Google Scholar 

  14. Fazakerley, J. & Walker, R. Virus demyelination. J. Neurovirol. 9, 148–164 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tsunoda, I. & Fujinami, R. Theiler's murine encephalomyelitis virus. In Persistent Viral Infections (eds Ahmed, R. & Chen, I.) 517–536 (John Wiley, New York, 1999).

    Google Scholar 

  16. Marten, N. W., Stohlman, S. A. & Bergmann, C. C. MHV infection of the CNS: mechanisms of immune-mediated control. Viral Immunol. 14, 1–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Stohlman, S., Bergmann, C. & Perlman, S. Mouse hepatitis virus. In Persistent Viral Infection (eds Ahmed, R. & Chen, I.) 537–558 (John Wiley, New York, 1999).

    Google Scholar 

  18. Perlman, S. Pathogenesis of coronavirus-induced infections: review of pathological and immunological aspects. Adv. Exp. Med. Biol. 440, 503–513 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Trotter, M., Schlitt, B. P., Kung, A. Y. & Lipton, H. L. Transition from acute to persistent Theiler's virus infection requires active viral replication that drives proinflammatory cytokine expression and chronic demyelinating disease. J. Virol. 78, 12480–12488 (2004).

    Article  CAS  Google Scholar 

  20. Croxford, J. L., Olson, J. K. & Miller, S. D. Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler's virus-induced demyelinating disease model of multiple sclerosis. Autoimmun. Rev. 1, 251–260 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H. & Miller, S. D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med. 11, 252–253 (2005).

    Article  CAS  Google Scholar 

  22. Stadler, K. et al. SARS β€” beginning to understand a new virus. Nature Rev. Microbiol. 1, 209–218 (2003).

    Article  CAS  Google Scholar 

  23. Williams, R. K., Jiang, G. S., Snyder, S. V., Frana, M. F. & Holmes, K. V. Purification of the 110-dilodalton glycoprotein receptor for mouse hepatitis virus (MHV)-A59 and identification of a non-functional, homologous protein MHV-resistant SJL/J mice. J. Virol. 64, 3817–3823 (1990). This paper is the first to describe the host-cell receptor for murine coronaviruses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Parker, S. E., Gallagher, T. M. & Buchmeier, M. J. Sequence analysis reveals extensive polymorphism and evidence of deletions within the E2 glycoprotein gene of several strains of murine hepatitis virus. Virology 173, 664–673 (1989). This study was the first to clearly identify a polymorphic region of the S protein in different strains of MHV. These observations provided the potential for understanding viral determinants of pathogenicity at the molecular level.

    Article  CAS  PubMed  Google Scholar 

  25. Fleming, J. O., Trousdale, M., El-Zaatari, F., Stohlman, S. A. & Weiner, L. P. Pathogenicity of antigenic variants of murine coronavirus JHM selected with monoclonal antibodies. J. Virol. 58, 869–875 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Phillips, J. J., Chua, M. M., Lavi, E. & Weiss, S. R. Pathogenesis of chimeric MHV4/MHV-A59 recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence. J. Virol. 73, 7752–7760 (1999). Recombinant technology that replaced the viral S proteins and analysis of subsequent pathogenesis showed that the S protein is a major determinant of coronavirus-induced CNS disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chua, M., MacNamara, K., Mateo, L., Shen, H. & Weiss, S. Effects of an epitope specific CD8+T cell response on murine central nervous system disease: protection from virus replication and antigen spread and selection of epitope escape mutants. J. Virol. 78, 1150–1159 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. MacNamara, K., Chua, M., Phillips, J. & Weiss, S. Contributions of viral genetic background and a single amino acid substitution in an immunodominant CD8+ T cell epitope to murine coronavirus neurovirulence. J. Virol. 79, 9108–9118 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, W. & Baric, R. S. Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased host cell resistance and virus virulence. J. Virol. 70, 3947–3960 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gallagher, T. M., Buchmeier, M. J. & Perlman, S. Cell receptor-independent infection by a neurotropic murine coronavirus. Virology 191, 517–522 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Gallagher, T. & Buchmeier, M. Coronavirus spike proteins in viral entry and pathogenesis. Virology 279, 371–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Morales, S., Parra, B., Ramakrishna, C., Blau, D. & Stohlman, S. B cell mediated lysis of cells infected with the neurotropic JHM strain of mouse hepatitis virus. Virology 286, 160–167 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Nakagaki, K., Nakagaki, K. & Taguchi, F. Receptor-independent spread of a high neurotropic murine coronavirus JHMV strain from initially infected microglial cells in mixed neural cultures. J. Virol. 79, 6102–6110 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ontiveros, E., Kim, T. S., Gallagher, T. M. & Perlman, S. Enhanced virulence mediated by the murine coronavirus, mouse hepatitis strain JHM, is associated with a glycine at residue 310 of the spike glycoprotein. J. Virol. 77, 10260–10269 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ramakrishna, C., Bergmann, C., Holmes, K. V. & Stohlman, S. Expression of the mouse hepatitis virus receptor by central nervous system microglia. J. Virol. 78, 7828–7832 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, F. I., Hinton, D. R., Gilmore W., Trousdale, M. D. & Fleming, J. O. Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination. Lab. Invest. 66, 744–754 (1992).

    CAS  PubMed  Google Scholar 

  37. Zhou, J., Stohlman, S., Hinton, D. R. & Marten, N. Neutrophils modulate inflammation during viral induced encephalitis. J. Immunol. 170, 3331–3336 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Lin, M., Stohlman, S. & Hinton, D. Mouse hepatitis virus is cleared from the central nervous system of mice lacking perforin-mediated cytolysis. J. Virol. 71, 383–391 (1997). The authors provide the initial evidence that perforin-mediated cytolysis controls virus replication in only a subset of CNS cells during acute infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Parra, B. et al. g interferon is required for viral clearance from central nervous system oligodendroglia. J. Immunol. 162, 1641–1647 (1999). This report shows the crucial role of IFN-Ξ³ in coronavirus-induced CNS disease and provides the first evidence that separate effector mechanisms control virus replication within a single target, the CNS.

    CAS  PubMed  Google Scholar 

  40. Bergmann, C., Altman, J., Hinton, D. & Stohlman, S. Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the CNS. J. Immunol. 163, 3379–3387 (1999). One of the first reports of the application of tetramer technology to an infectious disease. The data quantify both recruitment and retention of virus-specific CD8+ T cells in the CNS.

    CAS  PubMed  Google Scholar 

  41. Lane, T. E. et al. A central role for CD4+ T cells and RANTES in virus-induced central nervous system inflammation and demyelination. J. Virol. 74, 1415–1424 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wu, G. F., Dandekar, A. A., Pewe, L. & Perlman, S. CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination. J. Immunol. 165, 2278–2286 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Marten, N., Stohlman, S. & Bergmann, C. Role of viral persistence in retaining CD8+ T cells within the central nervous system. J. Virol. 74, 7903–7910 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Adami, C. et al. Evolution of mouse hepatitis virus (MHV) during chronic infection: quasispecies nature of the persisting MHV RNA. Virology 209, 337–346 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Bergmann, C. C. et al. Variability of persisting MHV RNA sequences constituting immune and replication relevant domains. Virology 244, 563–572 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Bergmann, C. et al. Perforin mediated effector function within the CNS requires IFN-Ξ³ mediated MHC upregulation. J. Immunol. 170, 3204–3213 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Zhou, J. et al. Expression of matrix metalloproteinases and their tissue inhibitor during viral encephalitis. J. Virol. 79, 4764–4773 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lane, T. E. et al. Dynamic regulation of Ξ±- and Ξ²-chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J. Immunol. 160, 970–978 (1998).

    CAS  PubMed  Google Scholar 

  49. Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neuroscience 2, 502–511 (2001).

    Article  CAS  Google Scholar 

  50. Zhou, J., Stohlman, S., Atkinson, R., Hinton, D. & Marten, N. Matrix metalloproteinase expression correlates with virulence following neurotropic mouse hepatitis virus infection. J. Virol. 76, 7373–7384 (2002).

    Google Scholar 

  51. Ishihara, K. & Hirano, T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 13, 357–368 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Trifilo, M. J., Bergmann, C. C., Kuziel, W. A. & Lane, T. E. CC chemokine ligand 3 (CCL3) regulates CD8+-T-cell effector function and migration following viral infection. J. Virol. 77, 4004–4014 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Trifilo, M. J. et al. CXC chemokine ligand 10 controls viral infection in the central nervous system: evidence for a role in innate immune response through recruitment and activation of natural killer cells. J. Virol. 78, 585–594 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Glass, W. G. et al. Antibody targeting of the CC chemokine ligand 5 (CCL5) results in diminished leukocyte infiltration into the central nervous system and reduced neurologic disease in a viral model of multiple sclerosis. J. Immunol. 172, 4018–4025 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Asensio, V. C. & Campbell, I. L. Chemokine gene expression in the brains of mice with lymphocytic choriomeningitis. J. Virol. 71, 7832–7840 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hoffman, L. M., Fife, B. T., Begolka, W. S., Miller, S. D. & Karpus, W. J. Central nervous system chemokine expression during Theiler's virus-induced demyelinating disease. J. Neurovirol. 5, 635–642 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Manchester, M., Eto, D. S. & Oldstone, M. B. Characterization of the inflammatory response during acute measles encephalitis in NSE-CD46 transgenic mice. J. Neuroimmunol. 96, 207–217 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Salazar-Mather, T. P., Lewis, C. A. & Biron, C. A. Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1Ξ± delivery to the liver. J. Clin. Invest. 110, 321–330 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pearce, B. D., Hobbs, M. V., McGraw, T. S. & Buchmeier, M. J. Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. J. Virol. 68, 5483–5495 (2004).

    Article  Google Scholar 

  60. Parra, B., Hinton, D. R., Lin, M. T., Cua, D. J. & Stohlman, S. A. Kinetics of cytokine mRNA expression in the CNS following lethal and sublethal coronavirus-induced encephalomyelitis. Virology 233, 260–270 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Rempel, J. D., Murray, S. J., Meisner, J. & Buchmeier. M. J. Differential regulation of innate and adaptive immune responses in viral encephalitis. Virology 318, 381–392 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Rempel, J. D., Quina, L. A., Blakelu-Gonzales, P. K., Buchmeier, M. J. & Gruol, D. L. Viral induction of central nervous system innate immune responses. J. Virol. 79, 4369–4381 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lane, T. E. & Buchmeier, M. J. Chemokine responses in virus-induced neurologic disease: balancing host defense and neuropathology. In Universe In Delicate Balance: Chemokines And The Nervous System (ed. Ransohoff, R.) 191–202 (Elsevier, Amsterdam, 2002).

    Chapter  Google Scholar 

  64. Asensio, V. C. & Campbell, I. L. Chemokines and viral diseases of the central nervous system. Adv. Virus Res. 56, 127–173 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Biron, C. A. Role of early cytokines, including Ξ± and Ξ² interferons (IFN-Ξ±/Ξ²), in innate and adaptive immune responses to viral infections. Semin. Immunol. 10, 383–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Lane, T. E., Paoletti, A. D. & Buchmeier, M. J. Disassociation between the in vitro and in vivo effects of nitric oxide on a neurotropic murine coronavirus. J. Virol. 71, 2202–2210 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lane, T. E., Fox, H. S. & Buchmeier, M. J. Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and inflammation. J. Neurovirol. 5, 48–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Wu, G. F., Pewe, L. & Perlman, S. Coronavirus-induced demyelination occurs in the absence of inducible nitric oxide synthase. J. Virol. 74, 7683–7686 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen, B. P. & Lane, T. E. Lack of nitric oxide synthase type 2 (NOS2) results in reduced neuronal apoptosis and mortality following mouse hepatitis virus infection of the central nervous system. J. Neurovirol. 8, 58–63 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Stohlman, S. A. et al. Tumor necrosis factor expression during mouse hepatitis virus induced demyelination. J. Virol. 69, 5898–5903 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sacca, R., Cuff, C. A. & Ruddle, N. H. Mediators of inflammation. Curr. Opin. Immunol. 9, 851–857 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Pewe, L. & Perlman, S. Cutting edge: CD8 T cell-mediated demyelination is IFN-Ξ³ dependent in mice infected with a neurotropic coronavirus. J. Immunol. 168, 1547–1551 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Stevenson, P. G., Hawke, S., Sloan, D. J. & Bangham, C. R. M. The immunogenicity of intracerebral virus-infection depends on anatomical site. J. Virol. 71, 145–151 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lowenstein, P. R. Immunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Trends Immunol. 23, 23–30 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Marten, N., Stohlman, S., Zhou, Z. & Bergmann, C. Kinetics of virus specific CD8+T cell expansion and trafficking following central nervous system infection. J. Virol. 77, 2775–2778 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Med. 11, 328–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Trifilo, J. J. & Lane, T. E. The CC chemokine ligand 3 regulates CD11c+CD11b+CD8Ξ±-dendritic cell maturation and activation following viral infection of the central nervous system: implications or a role in T cell activation. Virology 327, 8–15 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Liu, M. T. et al. Cutting edge: the T cell chemoattractant IFN-inducible protein 10 (IP-10) is essential in host defense against viral-induced neurologic disease. J. Immunol. 165, 2327–2330 (2000). This paper was the first to show that expression of CXCL10 within the CNS in response to viral infection was crucial in host defence by attracting virus-specific T cells.

    Article  CAS  PubMed  Google Scholar 

  79. Liu, M. T., Armstrong, D., Hamilton, D. A. & Lane, T. E. Expressing of Mig (monokine induced by interferon Ξ³) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. J. Immunol. 166, 1790–1795 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Chen, A. M., Khanna, N., Stohlman, S. A. & Bergmann, C. C. Virus-specific and bystander CD8 T cells recruited during virus-induced encephalomyelitis. J. Virol. 79, 4700–4708 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bergmann, C. et al. Perforin and interferon Ξ³ mediated control of coronavirus central nervous system infection by CD8 T cells in the absence of CD4 T cells. J. Virol. 78, 1739–1750 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stohlman, S. A., Bergmann, C. C., Lin, M. T., Cua, D. J. & Hinton, D. R. CTL effector function within the CNS requires CD4+ T cells. J. Immunol. 160, 2896–2904 (1998).

    CAS  PubMed  Google Scholar 

  83. Zhou, J., Hinton, D. R., Stohlman, S. A. & Marten, N. Maintenance of CD8+ T cells during acute viral infection of the central nervous system requires CD4+ T cells but not interleukin-2. Virol. Immunol. 18, 162–169 (2005).

    Article  CAS  Google Scholar 

  84. Hawke, S., Stevenson, P. G., Freeman, S. & Bangham, C. R. M. Long term persistence of activated cytotoxic T lymphocytes after viral infection of the central nervous system. J. Exp. Med. 187, 1575–1582 (1998). The authors show that activated virus-specific CD8+ T cells derived from a memory population are retained within the CNS in the absence of viral antigen. Antigen-specific T cells can persist and retain effector function within tissues of relative immune privilege, and might be important for efficient control of viral recrudescence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ramakrishna, C., Stohlman, S., Atkinson, R., Hinton, D. H. & Bergmann, C. C. Differential regulation of primary and secondary CD8+ T cells in the CNS. J. Immunol. 173, 6265–6273 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. John, B. & Crispe, I. N. Passive and active mechanisms trap activated CD8+ T cells in the liver. J. Immunol. 172, 5222–5229 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Parra, B. et al. Contributions of Fas–Fas ligand interactions to the pathogenesis of mouse hepatitis virus in the central nervous system. J. Virol. 74, 2447–2450 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gonzalez, J. M. et al. Expression of a dominant negative IFN-Ξ³ receptor on mouse oligodendrocytes. Glia 51, 22–34 (2005).

    Article  PubMed  Google Scholar 

  89. Harty, J. T., Tvinnereim, A. R. & White, D. W. CD8+ T cell effector mechanisms in resistance to infection. Annu. Rev. Immunol. 18, 275–308 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Rowe, C. L. et al. Generation of Coronavirus spike deletion variants by high frequency recombination at regions of predicted RNA secondary structure. J Virol. 71, 6183–6190 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pewe, L., Wu, G. F., Barnett, E. M., Castro, R. F. & Perlman, S. Cytotoxic T cell-resistant variants are selected in a virus-induced demyelinating disease. Immunity 5, 253–262 (1996). These authors provide the first evidence that CD8+ T-cell escape mutants that evade the developing immune system are the basis for coronavirus reactivation within the CNS of mice infected as neonates and protected by maternal antibody.

    Article  CAS  PubMed  Google Scholar 

  92. Lefrancois, L. & Masopust, D. T cell immunity in lymphoid and non-lymphoid tissues. Curr. Opin. Immunol. 14, 503–508 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Masopust, D. & Ahmed, R. Reflections on CD8 T-cell activation and memory. Immunol. Res. 29, 151–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Marten, N. et al. Selection of CD8+ T cells with highly focused specificity during viral persistence in the central nervous system. J. Immunol. 162, 3905–3914 (1999).

    CAS  PubMed  Google Scholar 

  95. Fleming, J. O., Shubin, R. A., Sussman, M. A., Casteel, N. & Stohlman, S. A. Monoclonal antibodies to the matrix (E1) glycoprotein of mouse hepatitis virus protect mice from encephalitis. Virology 168, 162–167 (1988).

    Article  Google Scholar 

  96. Kyuwa, S., Cohen, M., Nelson, G., Tahara, S. & Stohlman, S. A. Modulation of macromolecular synthesis by coronavirus: implications for pathogenicity. J. Virol. 68, 6815–6819 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lin, M. T., Hinton, D. R., Marten, N. W., Bergmann, C. C. & Stohlman, S. A. Antibody prevents virus reactivation within the central nervous system. J. Immunol. 162, 7358–7368 (1999).

    CAS  PubMed  Google Scholar 

  98. Ramakrishna, C., Stohlman, S., Atkinson, R., Schlomchik, M. & Bergmann, C. Mechanisms of central nervous system viral persistence: critical role of antibody and B cells. J. Immunol. 168, 1204–1211 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Matthews, A. E. et al. Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver. J. Immunol. 167, 5254–5263 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Ramakrishna, C., Bergmann, C., Atkinson, R. & Stohlman, S. Control of central nervous system viral persistence by neutralizing antibody. J. Virol. 77, 4670–4678 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tschen, S. I., Bergmann, C., Ramakrishna, C., Atkinson, R. & Stohlman, S. Recruitment kinetics of antibody secreting cells within the CNS following viral encephalomyelitis. J. Immunol. 168, 2922–2929 (2002). References 100 and 101 show that virus-specific ASCs are recruited and retained in the CNS after acute virus infection is controlled and, importantly, that neutralizing antibody is the crucial effector in controlling a chronic coronavirus infection of the CNS.

    Article  CAS  PubMed  Google Scholar 

  102. Tyor, W. R. & Griffin, D. E. Virus specificity and isotype expression of intraparenchymal antibody-secreting cells during Sindbis virus encephalitis in mice. J. Neuroimmunol. 48, 37–44 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mokhtarian, F., Huan, C. M., Roman, C. & Raine, C. S. Semliki Forest virus-induced demyelination and remyelination β€” involvement of B cells and anti-myelin antibodies. J. Neuroimmunol. 137, 19–31 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Redwine, J. M., Buchmeier, M. J. & Evans, C. F. In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. Amer. J. Pathol. 159, 1219–1224 (2001).

    Article  CAS  Google Scholar 

  105. Tyler, K. & Gonzalez-Scarano, F. Viral diseases of the central nervous system: acute infection. In Viral Pathogenesis (ed. Nathanson, N.) 837–854 (Lippincott–Rave, Philadelphia, 1997).

    Google Scholar 

  106. Gu, J. et al. Multiple organ infection and the pathogenesis of SARS. J. Exp. Med. 202, 415–424 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Stohlman, S. A., Fleming, J. O., Brayton, P. R., Weiner, L. P. & Lai, M. M. C. Murine coronaviruses: isolation and characterization of two plaque morphology variants of the JHM neurotropic strain. J. Gen. Virol. 63, 265–275 (1982).

    Article  CAS  PubMed  Google Scholar 

  108. Navas, S. & Weiss, S. R. Murine coronavirus-induced hepatitis: JHM genetic background eliminates A59 spike-determined hepatotropism. J. Virol. 77, 4972–4978 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rempel, J. D., Murray, S. J., Meisner, J. & Buchmeier, M. J. Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology. Virology 318, 45–54 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health grants.

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Authors and Affiliations

  1. Cleveland Clinic Foundation, Neurosciences, 9500 Euclid Avenue NC30, Cleveland, 44195, Ohio, USA

    Cornelia C. Bergmann & Stephen A. Stohlman

  2. University of California, Irvine, Molecular Biology & Biochemistry, 3205 McGaugh Hall, Irvine, 92697, California, USA

    Thomas E. Lane

Authors
  1. Cornelia C. Bergmann
  2. Thomas E. Lane
  3. Stephen A. Stohlman

Corresponding author

Correspondence to Stephen A. Stohlman.

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Competing interests

The authors declare no competing financial interests.

Glossary

Neurotrophins

A large family of proteins required for cell survival and differentiation within the vertebrate nervous system.

Blood–brain barrier

(BBB). Permeability barrier that comprises endothelial cells that line cerebral capillaries. Regulates the transport of cells and large-molecule transport into the CNS parenchyma.

Tight junctions

Intercellular junctions where adjacent plasma membranes are joined and occlude the intercellular space, resulting in limited intercellular passage of molecules.

Ependymal cells

Cells that line the CNS ventricles as a single cell layer.

Chemokines

Small, mostly soluble proteins that induce directional migration of innate and adaptive immune cells to sites of infection or injury.

Matrix metalloproteinases

(MMPs). Proteases that contribute to tissue remodelling, wound healing and cell trafficking. MMPs enhance the activity of cytokines and growth factors but also degrade these factors.

Tissue inhibitors of MMPs

(TIMPs). A small family of specific matrix metalloproteinase (MMP) inhibitors that regulate MMP activity.

Cytokine

A member of a large family of secreted proteins that bind immune cells through specific receptors. Cytokine production results in the activation of an intracellular-signalling cascade that commonly regulates processes such as immune function and inflammation.

Type I interferons

Interferons IFN-Ξ± and IFN-Ξ², produced by most nucleated cells to resist viral replication. By contrast, type II interferon (IFN-Ξ³) is secreted by activated T cells and NK cells and activates many responding cell types, including macrophages and microglia.

Adaptive Immunity

Represented by B and T cells that express antigen-specific receptors. Memory lymphocytes persist, providing lifetime immunity against re-infection.

Innate immunity

The first line of defence after infection. Macrophages, neutrophils and natural killer cells as well as acute-phase proteins and cytokines participate partly by signalling through non-antigen-specific receptors, including Toll-like receptors.

Cerebrospinal fluid

Fluid produced by the secretory epithelium of the choroid plexus, which lines the ventricles of the brain.

CNS parenchyma

Tissue space occupied by resident cells of the CNS and separated from peripheral space by the blood–brain-barrier.

Perforin-mediated cytolysis

The release of perforin and granzymes from stored granules within cytotoxic T cells and NK cells on contact with target cells, resulting in death, primarily by apoptosis.

Fas/FasL cytolytic pathway

Signalling pathway evoked by binding of Fas ligand (FasL) on surface of effector cell to Fas (a member of the TNF receptor family) expressed on surface of target cells, inducing apoptosis of the Fas-bearing cell.

Anergy

State of non-responsiveness of T cells and B cells characterized by their inability to respond to specific antigen under optimal stimulation conditions.

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Bergmann, C., Lane, T. & Stohlman, S. Coronavirus infection of the central nervous system: host–virus stand-off. Nat Rev Microbiol 4, 121–132 (2006). https://doi.org/10.1038/nrmicro1343

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