The Journal of Experimental Medicine
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Published 17 October 2005. doi:10.1084/jem.20042530
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 8, 1087-1098
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ARTICLE

 Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection

William G. Glass1, Jean K. Lim1, Rushina Cholera1, Alexander G. Pletnev2, Ji-Liang Gao1, and Philip M. Murphy1

1 Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
2 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE Philip M. Murphy: pmm{at}nih.gov

The molecular immunopathogenesis of West Nile virus (WNV) infection is poorly understood. Here, we characterize a mouse model for WNV using a subcutaneous route of infection and delineate leukocyte subsets and immunoregulatory factors present in the brains of infected mice. Central nervous system (CNS) expression of the chemokine receptor CCR5 and its ligand CCL5 was prominently up-regulated by WNV, and this was associated with CNS infiltration of CD4+ and CD8+ T cells, NK1.1+ cells and macrophages expressing the receptor. The significance of CCR5 in pathogenesis was established by mortality studies in which infection of CCR5–/– mice was rapidly and uniformly fatal. In the brain, WNV-infected CCR5–/– mice had increased viral burden but markedly reduced NK1.1+ cells, macrophages, and CD4+ and CD8+ T cells compared with WNV-infected CCR5+/+ mice. Adoptive transfer of splenocytes from WNV-infected CCR5+/+ mice into infected CCR5–/– mice increased leukocyte accumulation in the CNS compared with transfer of splenocytes from infected CCR5–/– mice into infected CCR5–/– mice, and increased survival to 60%, the same as in infected CCR5+/+ control mice. We conclude that CCR5 is a critical antiviral and survival determinant in WNV infection of mice that acts by regulating trafficking of leukocytes to the infected brain.

Abbreviations used: CNS, central nervous system; ffu, focus-forming unit; WNV, West Nile virus.

W.G. Glass and J.K. Lim contributed equally to this work.

W.G. Glass's present address is Centocor Global R&D, Infectious Diseases, Radnor, PA 19087.


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