Abstract
An effective host response against viral infection of the central nervous system (CNS) is the principal factor dictating the outcome of infection. It is the responsibility of the immune response to contain and control viral replication. Paradoxically, it is the immune response that may also contribute to the development of neuropathology. We have used mouse hepatitis virus (MHV), a positive-strand RNA virus, infection of the CNS to understand the dynamic interaction between viral replication, protection, and pathology with an emphasis on understanding how chemokines participate in these interrelated processes. Herein, we demonstrate the complexity of the chemokine response to MHV infection of the CNS and the delicate balance that exists between host defense and development of disease.
Key Words: Chemokines, Virus, T Lymphocytes, Macrophages, Demyelination
References
- 1.Lane TE, et al. A Central Role for CD4+ T Cells and RANTES in virus induced central nervous system inflammation and demyelination. J Virol. 2000;74:1415–1424. doi: 10.1128/JVI.74.3.1415-1424.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Liu MT, et al. Culting Edge: The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease. J Immunol. 2000;165:2327–2330. doi: 10.4049/jimmunol.165.5.2327. [DOI] [PubMed] [Google Scholar]
- 3.Liu MT, DA Amstrong, TA Hamilton, and TE Lane. Expression of Mig (Monokine Induced by Interon-γ) is Important in T Lymphocyte Recruitment and Host Defense Following Viral Infection of the Central Nervous System. J Immunol 2001; in press. [DOI] [PubMed]
- 4.Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338:436–436. doi: 10.1056/NEJM199802123380706. [DOI] [PubMed] [Google Scholar]
- 5.Premack B., Schall T. Chemokine receptors gateways to inflammation and infection. Nat Med. 1996;2:1174–1174. doi: 10.1038/nm1196-1174. [DOI] [PubMed] [Google Scholar]
- 6.Ward SG, Bacon K., Westwick J. Chemokines and T lymphocytes: more than an attraction. Immunity. 1998;9:1–11. doi: 10.1016/S1074-7613(00)80583-X. [DOI] [PubMed] [Google Scholar]
- 7.Kemedy KJ, Kampus WJ. Role of chemokines in the regulation of Th1/Th2 and autoimmune encephalomyelitis. J Clin Immunol. 1999;19(5):273–279. doi: 10.1023/A:1020535423465. [DOI] [PubMed] [Google Scholar]
- 8.Lane TE, et al. Dynamic regulation of alpha and beta chemokine expression in the central nervous system during mouse hepatitis virus-induced demyclinating disease. J Immunol. 1998;160:970–978. [PubMed] [Google Scholar]
- 9.Asensio VC, Camphell IL. Chemokine gene expression in the brains of mice with lymphocytic choriomeningitis. J Virol. 1997;71:7832–7840. doi: 10.1128/jvi.71.10.7832-7840.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Theil DJ, et al. Alterations in cytokine but not chemokine mRNA expression during three distinct Theiler's virus infections. J Neuroimmunol. 2000;104:22–30. doi: 10.1016/S0165-5728(99)00251-9. [DOI] [PubMed] [Google Scholar]
- 11.Murray PD, Krivacic K, Chernosky A, Wei T, Ransohoff RM, Rodriguez M. Biphasic and regionally-restricted chemokine expression in the central nervous system in the Theiler's virus model of multiple sclerosis. J Neurovirol. 2000;6(Suppl 1):44–52. [PubMed] [Google Scholar]
- 12.Perlman S, Lane T, Buchmeier M. Coronaviruses: Hepatitus, Peritonitis, and Central Nervous System Disease. In: Cummungham M., Fujinami R., editors. Effects of Microbes on the Immune System. Philadelphia, PA: Lippencott Williams & Wilkins; 2000. pp. 339–344. [Google Scholar]
- 13.Pearce BD, Hobbs MV, McGraw TS, Buchmeier MJ. Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. J Virol. 1994;68:5483–5495. doi: 10.1128/jvi.68.9.5483-5495.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Houtman JJ, Fleming JO. Pathogenesis of mouse hepatitis virus-induced demyelination. J Neurovirol. 1996;2:361–376. doi: 10.3109/13550289609146902. [DOI] [PubMed] [Google Scholar]
- 15.Wu GF, Perlman S. Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyclination following murine infection with a neurotropic coronavirus. J Virol. 1999;73(10):8771–8780. doi: 10.1128/jvi.73.10.8771-8780.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Yamaguchi K, Goto N, Kyuwa S, Hayami M, Toyoda Y. Protection of mice from a lethal coronavirus infection in the central nervous system by adoptive transfer of virus-specific T cell clones. J Neuroimmunol. 1991;32(1):1–9. doi: 10.1016/0165-5728(91)90065-F. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Stohlman SA, Bergman CC, van der Veen RC, and Hinton DR: Mouse hepatitis virus specific cytotoxic T lymphocytes protect from lethal infection without eliminating virus from the central nervous system. J Virol 1995; 69684. [DOI] [PMC free article] [PubMed]
- 18.Parra B, Hinton DR, Marien NW, Bergmann CC, Lin MT, Yang CS, Stohlman SA. IFN-gamma is required for viral cleatance from central nervous system oligodendroglia. J Immunol. 1999;162:1641–1647. [PubMed] [Google Scholar]
- 19.Lane TE, Paoletti AD, Buchmeier MJ. Disassociation between the in vitro and in vivo effects of nitric oxide on a neurotropic murine coronavirus. J. Virol. 1997;71:2202–10. doi: 10.1128/jvi.71.3.2202-2210.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Haspel M, Lampert P, Oldstone MBA. Temperature sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination. Proc Natl Acad Sci USA. 1978;75:4033–4036. doi: 10.1073/pnas.75.8.4033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Weiner LP. Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus) Arch Neurol. 1973;28:298–303. doi: 10.1001/archneur.1973.00490230034003. [DOI] [PubMed] [Google Scholar]
- 22.Wu GF, Dandekar AA, Pewe L, Perlman S. CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination. J Immunol. 2000;165(4):2278–2286. doi: 10.4049/jimmunol.165.4.2278. [DOI] [PubMed] [Google Scholar]
- 23.Wang FI, Stohlman SA, Fleming JO. Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated. J Neuroimmunol. 1990;30(1):31–41. doi: 10.1016/0165-5728(90)90050-W. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Biddison WE, et al. CD8+ myelin peptide-specific T cells can chemoattract CD4+ myeline peptide-specific T cells: importance of IFN-inducible protein 10. J Immunol. 1998;160:444–444. [PubMed] [Google Scholar]
- 25.Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Lewis IC, Baggiolini M, Moser B. Chemokine receptor specific for 1P-10 and Mig: structure, function, and expression in activated T-lymphocytes. J Exp Med. 1996;184:963–969. doi: 10.1084/jem.184.3.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J Leuk Biol. 1997;61:246–257. [PubMed] [Google Scholar]
- 27.Piali L, Wever C, Larasa G, Mackay CR, Springer TA, Clark-Lewis I, Moser B. The chemokine receptor CXCR3 mediates rapid and shear-resistant adhesion-induction of effector T lymphocytes by the chemokines IP-10 and Mig. Eur J Immunol. 1998;28:961–972. doi: 10.1002/(SICI)1521-4141(199803)28:03<961::AID-IMMU961>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
- 28.Lavi E, Wang Q. The protective role of cytotoxic T cells and interferon against coro-navirus in vasion of the brain. Adv Exp Med Biol. 1995;380:145–149. doi: 10.1007/978-1-4615-1899-0_24. [DOI] [PubMed] [Google Scholar]
- 29.Sussman MA, Shubin RA, Kyuwa S, Stohlman SA. T-cell-mediated clearance of mouse hepatitis virus strain JHM from the central nervous system. J Virol. 1989;63:3051–3056. doi: 10.1128/jvi.63.7.3051-3056.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990;347:669–671. doi: 10.1038/347669a0. [DOI] [PubMed] [Google Scholar]
- 31.Sorensen T., et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–815. doi: 10.1172/JCI5150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of the interferon-γ-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2000;26:133–142. doi: 10.1046/j.1365-2990.2000.026002133.x. [DOI] [PubMed] [Google Scholar]
- 33.Balashov K, Rottman J, Weiner H., Hancock W. CCR5(+) and CXCR3(+) T cells are increased in multiplesclesosis and their ligands MIP-1 alpha and IP=10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA. 1999;96:6873–6815. doi: 10.1073/pnas.96.12.6873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol. 1995;155:5003–5010. [PubMed] [Google Scholar]
- 35.Kennedy KJ, Stricter RM, Kunkel SL, Lukacs NW, Karpus WJ. Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1 alpha and monocyte chemotactic protein-1. J Neuroimmunol. 1998;92:98–108. doi: 10.1016/S0165-5728(98)00187-8. [DOI] [PubMed] [Google Scholar]