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,
,¶
* Division of Infectious Diseases,
Department of Pathology and Immunology,
Department of Medicine, Children’s Hospital of Boston, Boston, MA 02115; and
Department of Molecular Microbiology and
¶ Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110
Regional differences in inflammation during viral infections of the CNS suggest viruses differentially induce patterns of chemoattractant expression, depending on their cellular targets. Previous studies have shown that expression of the chemokine CXCL10 by West Nile virus (WNV)-infected neurons is essential for the recruitment of CD8 T cells for the purpose of viral clearance within the CNS. In the current study we used mice deficient for the CXCL10 receptor, CXCR3, to evaluate its role in leukocyte-mediated viral clearance of WNV infection within various CNS compartments. WNV-infected CXCR3-deficient mice exhibited significantly enhanced mortality compared with wild-type controls. Immunologic and virologic analyses revealed that CXCR3 was dispensable for control of viral infection in the periphery and in most CNS compartments but, surprisingly, was required for CD8 T cell-mediated antiviral responses specifically within the cerebellum. WNV-specific, CXCR3-expressing T cells preferentially migrated into the cerebellum, and WNV-infected cerebellar granule cell neurons expressed higher levels of CXCL10 compared with similarly infected cortical neurons. These results indicate that WNV differentially induces CXCL10 within neuronal populations and suggest a novel model for nonredundancy in chemokine-mediated inflammation among CNS compartments.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Midwest Regional Center for Excellence for Biodefense and Emerging Infectious Diseases Grant 5U54 AI057160 (to R.S.K.), and National Institutes of Health/National Institute of Neurological Disorders and Stroke Grants K02NS045607 (to R.S.K.) and R01NS052632 (to R.S.K. and M.S.D.). The work cited in this publication was performed in a facility supported by the NCRR grant C06 RR012466.
2 Address correspondence and reprint requests to Dr. Robyn S. Klein, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: rklein{at}id.wustl.edu
3 Abbreviations used in this paper: MHV, mouse hepatitis virus; LCMV, lymphocytic choriomeningitis virus; WNV, West Nile virus.
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