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* Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan;
Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan;
Department of Pediatrics, Children’s Hospital, Harvard Medical School, Boston, MA 02115; and
¶ Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
We examined the extent to which CXCR3 mediates resistance to dengue infection. Following intracerebral infection with dengue virus, CXCR3-deficient (CXCR3–/–) mice showed significantly higher mortality rates than wild-type (WT) mice; moreover, surviving CXCR3–/– mice, but not WT mice, often developed severe hind-limb paralysis. The brains of CXCR3–/– mice showed higher viral loads than those of WT mice, and quantitative analysis using real-time PCR, flow cytometry, and immunohistochemistry revealed fewer T cells, CD8+ T cells in particular, in the brains of CXCR3–/– mice. This suggests that recruitment of effector T cells to sites of dengue infection was diminished in CXCR3–/– mice, which impaired elimination of the virus from the brain and thus increased the likelihood of paralysis and/or death. These results indicate that CXCR3 plays a protective rather than an immunopathological role in dengue virus infection. In studies to identify critical CXCR3 ligands, CXCL10/IFN-inducible protein 10-deficient (CXCL10/IP-10–/–) mice infected with dengue virus showed a higher mortality rate than that of the CXCR3–/– mice. Although CXCL10/IP-10, CXCL9/monokine induced by IFN-
, and CXCL11/IFN-inducible T cell 
chemoattractant share a single receptor and all three of these chemokines are induced by dengue virus infection, the latter two could not compensate for the absence of CXCL10/IP-10 in this in vivo model. Our results suggest that both CXCR3 and CXCL10/IP-10 contribute to resistance against primary dengue virus infection and that chemokines that are indistinguishable in in vitro assays differ in their activities in vivo.
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