Lack of CCR2 results in increased mortality and impaired leukocyte activation and trafficking following infection of the central nervous system with a neurotropic coronavirus.
In the present study, we evaluated the role of CCR2 in a model of viral-induced neurologic disease. An orchestrated expression of chemokines, including the CCR2 ligands monocyte chemoattractant protein-1/CCL2 and monocyte chemoattractant protein-3/CCL7, occurs within the CNS following infection with mouse hepatitis virus (MHV). Infection of mice lacking CCR2 (CCR2(-/-)) with MHV resulted in increased mortality and enhanced viral recovery from the brain that correlated with reduced (p < or = 0.04) T cell and macrophage/microglial (determined by F4/80 Ag expression, p < or = 0.004) infiltration into the CNS. Moreover, MHV-infected CCR2(-/-) mice displayed a significant decrease in Th1-associated factors IFN-gamma (p < or = 0.001) and RANTES/CCL5 (p < or = 0.002) within the CNS as compared with CCR2(+/+) mice. Further, peripheral CD4(+) and CD8(+) T cells from immunized CCR2(-/-) mice displayed a marked reduction in IFN-gamma production in response to viral Ag and did not migrate into the CNS of MHV-infected recombination-activating gene (RAG)1(-/-) mice following adoptive transfer. In addition, macrophage/microglial infiltration into the CNS of RAG1(-/-) mice receiving CCR2(-/-) splenocytes was reduced (p < or = 0.05), which correlated with a reduction in the severity of demyelination (p < or = 0.001) as compared with RAG1(-/-) mice receiving splenocytes from CCR2(+/+) mice. Collectively, these results indicate an important role for CCR2 in host defense and disease by regulating leukocyte activation and trafficking.
Chen
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BP
Department of Molecular Biology and Biochemistry and Reeve-Irvine Research Center, University of California, Irvine, CA 92612, USA.
Kuziel
W A
WA
Lane
T E
TE
D000818:Animals; D002465:Cell Movement; D020805:Central Nervous System Viral Diseases / Q000276:immunology* / Q000401:mortality; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D018352:Coronavirus Infections / Q000276:immunology* / Q000401:mortality; D007962:Leukocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000276:immunology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency*; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D019562:Viral Load
C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine