Skip to main content
PMC home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 2002 May 25;288(1):8–17. doi: 10.1006/viro.2001.1050

Reduced Macrophage Infiltration and Demyelination in Mice Lacking the Chemokine Receptor CCR5 Following Infection with a Neurotropic Coronavirus

William G Glass a, Michael T Liu a, William A Kuziel b, Thomas E Lane a,c,1
PMCID: PMC7142305  PMID: 11543653

Abstract

Studies were performed to investigate the contributions of the CC chemokine receptor CCR5 in host defense and disease development following intracranial infection with mouse hepatitis virus (MHV). T cell recruitment was impaired in MHV-infected CCR5−/− mice at day 7 postinfection (pi), which correlated with increased (P ≤ 0.03) titers within the brain. However, by day 12 pi, T cell infiltration into the CNS of infected CCR5−/− and CCR5+/+ mice was similar and both strains exhibited comparable viral titers, indicating that CCR5 expression is not essential for host defense. Following MHV infection of CCR5+/+ mice, greater than 50% of cells expressing CCR5 antigen were activated macrophage/microglia (determined by F4/80 antigen expression). In addition, infected CCR5−/− mice exhibited reduced (P ≤ 0.02) macrophage (CD45highF4/80+) infiltration, which correlated with a significant reduction (P ≤ 0.001) in the severity of demyelination compared to CCR5+/+ mice. These data indicate that CCR5 contributes to MHV-induced demyelination by allowing macrophages to traffic into the CNS.

Keywords: chemokine, chemokine receptor, demyelination, multiple sclerosis, macrophage, neuroimmunology

References

REFERENCES

  • 1.Andres P.E., Beck P.L., Mizoguchi A., Bhan A.K., Dawson T., Kuziel W.A., Maeda N., MacDermott R.P., Podolsky D.K., Reinecker H. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitus: Lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte associated Th2-type immune response in the intestine. J. Immunol. 2000;164:6303–6312. doi: 10.4049/jimmunol.164.12.6303. [DOI] [PubMed] [Google Scholar]
  • 2.Boring L., Gosling J., Monteclaro F.S., Lusis A.J., Tsou C., Charo I.F. Molecular cloning and functional expression of murine JE (monocyte chemoattractant protein 1) and murine macrophage inflammatory protein 1α receptors. J. Biol. Chem. 1996;271:7551–7558. doi: 10.1074/jbc.271.13.7551. [DOI] [PubMed] [Google Scholar]
  • 3.Dalziel R., Lampert P., Buchmeier M. Site-specific alteration of murine hepatitis virus type 4 polymer glycoprotein E2 results in reduced neurovirulence. J. Virol. 1986;59:463–471. doi: 10.1128/jvi.59.2.463-471.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Dawson T.C., Beck M.A., Kuziel W.A., Henderson F., Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am. J. Pathol. 2000;156:1951–1959. doi: 10.1016/S0002-9440(10)65068-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Domachowske J.B., Bonville C.A., Gao J.L., Murphy P.M., Easton A.J., Rosenberg H.F. The chemokine macrophage-inflammatory protein-1 alpha and its receptor CCR1 control pulmonary inflammation and antiviral host defense in paramyxovirus infection. J. Immunol. 2000;165:2677–2682. doi: 10.4049/jimmunol.165.5.2677. [DOI] [PubMed] [Google Scholar]
  • 6.Dorf M.E., Berman M.A., Tanabe S., Heesen M., Lou Y. Astrocytes express functional chemokine receptors. J. Neuroimmunol. 2000;111:109–121. doi: 10.1016/s0165-5728(00)00371-4. [DOI] [PubMed] [Google Scholar]
  • 7.Fife B.T., Huffnagle G.B., Kuziel W.A., Karpus W.J. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 2000;192:899–905. doi: 10.1084/jem.192.6.899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Ford A.L., Goodsall A.L., Hickey W.F., Sedgwick J.D. Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J. Immunol. 1995;154:4309–4321. [PubMed] [Google Scholar]
  • 9.Hirano N., Murakami T., Fujiwara K., Matsumoto M. Utility of the mouse cell line DBT for propagation and assay of mouse hepatitis virus. Jpn. J. Exp. Med. 1978;48:71–75. [PubMed] [Google Scholar]
  • 10.Houtman J., Fleming J.O. Pathogenesis of mouse hepatitis virus-induced demyelination. J. Neurovirol. 1996;2:361–367. doi: 10.3109/13550289609146902. [DOI] [PubMed] [Google Scholar]
  • 11.Huffnagle G.B., McNeil L.K., McDonald R.A., Murphy J.W., Toews G.B., Maeda N., Kuziel W.A. Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cyptococcus neoformans. J. Immunol. 1999;163:4642–4646. [PubMed] [Google Scholar]
  • 12.Kennedy K.J., Strieter R.M., Kunkel S.L., Lukacs N.W., Karpus W.J. 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]
  • 13.Lane T.E., Buchmeier M.J. Murine coronavirus infection: A paradigm for virus-induced demyelinating disease. Trends Microbiol. 1997;5:9. doi: 10.1016/S0966-842X(97)81768-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Lane T.E., Asensio V., Yu N., Paoletti A., Campbell I., Buchmeier M.J. Dynamic regulation of alpha and beta chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J. Immunol. 1998;160:970–978. [PubMed] [Google Scholar]
  • 15.Lane T.E., Liu M.T., Chen B.P., Asensio V.C., Samawi R.M., Paoletti A.D., Campbell I.L., Kunker S.L., Fox H.S., Buchmeier M.J. 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]
  • 16.Lin M.T., Stohlman S.A., Hinton D.R. Mouse hepatitis virus is cleared from the central nervous systems of mice lacking perforin-mediated cytolysis. J. Virol. 1997;71:383–391. doi: 10.1128/jvi.71.1.383-391.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Liu M., Chen B., Oertel P., Buchmeier M., Armstrong D., Hamilton T., Lane T.E. Cutting 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]
  • 18.Liu M.T., Armstrong D., Hamilton T.A., Lane T.E. Expression of MIG (monokine induced by interferon-gamma) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. J. Immunol. 2001;166:1790–1795. doi: 10.4049/jimmunol.166.3.1790. [DOI] [PubMed] [Google Scholar]
  • 19.Mack M., Cihak J., Simonis C., Luckow B., Proudfoot A.E., Plachy J., Bruhl H., Frink M., Anders H.J., Vielhauer V., Pfirstinger J., Stangassinger M., Schlondorff D. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 2001;166:4697–4704. doi: 10.4049/jimmunol.166.7.4697. [DOI] [PubMed] [Google Scholar]
  • 20.Meyer A., Coyle A.J., Proudfoot A.E.I., Wells T.N.C., Power C.A. Cloning and characterization of a novel murine macrophage inflammatory protein-1α receptor. J. Biol. Chem. 1996;271:14445–14451. doi: 10.1074/jbc.271.24.14445. [DOI] [PubMed] [Google Scholar]
  • 21.Murphy P.M., Baggiolini M., Charo I.F., Hebert C.A., Horuk R., Matsushima K., Miller L.H., Oppenheim J.J., Power C.A. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 2000;52:145–176. [PubMed] [Google Scholar]
  • 22.Raport C.J., Gosling J., Schweickart V.L., Gray P.W., Charo I.F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1α and MIP-1β. J. Biol. Chem. 1996;271:17161–17166. doi: 10.1074/jbc.271.29.17161. [DOI] [PubMed] [Google Scholar]
  • 23.Sallusto F., Mackay C.R., Lanzavecchia A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu. Rev. Immunol. 2000;177:593–620. doi: 10.1146/annurev.immunol.18.1.593. [DOI] [PubMed] [Google Scholar]
  • 24.Sato N., Kuziel W., Melby C., Reddick R., Kostecki V., Zhao W., Maeda N., Ahuja S., Ahuja S.S. Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice. J. Immunol. 1999;163:5519–5525. [PubMed] [Google Scholar]
  • 25.Siebert H., Sachse A., Kuziel W.A., Maeda N., Bruck W. The chemokine receptor CCR2 is involved in macrophage recruitment to the injured peripheral nervous system. J. Neuroimmunol. 2000;110:177–185. doi: 10.1016/s0165-5728(00)00343-x. [DOI] [PubMed] [Google Scholar]
  • 26.Tran E.H., Kuziel W.A., Owens T. Induction of experiental autoimune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1α or its CCR5 receptor. Eur. J. Immunol. 2000;30:1410–1415. doi: 10.1002/(SICI)1521-4141(200005)30:5<1410::AID-IMMU1410>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  • 27.Williamson J.S., Stohlman S.A. Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells. J. Virol. 1990;64:4589–4592. doi: 10.1128/jvi.64.9.4589-4592.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Wu G.F., Perlman S. Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus. J. Virol. 1999;73:8771–8780. doi: 10.1128/jvi.73.10.8771-8780.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.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. 2000;165:2278–2286. doi: 10.4049/jimmunol.165.4.2278. [DOI] [PubMed] [Google Scholar]
  • 30.Zhou Y., Kurihara T., Ryseck R., Yang Y., Ryan C., Loy J., Warr G., Bravo R. Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homolouge of the major HIV-1 coreceptor. J. Immunol. 1998;160:4018–4025. [PubMed] [Google Scholar]
  • 31.Zlotnik A., Yoshie O. Chemokines: A new classification system and their role in immunity. Immunity. 2000;12:121–127. doi: 10.1016/s1074-7613(00)80165-x. [DOI] [PubMed] [Google Scholar]

Articles from Virology are provided here courtesy of Elsevier

RESOURCES