title: Both CXCR3 and CXCL10/IFN-inducible protein 10 are required for resistance to primary infection by dengue virus.
abstract: 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-gamma, and CXCL11/IFN-inducible T cell alpha 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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Hsieh
authors.forename: Szu-Liang
authors.initials: SL
authors.lastname: Lai
authors.forename: Jia-Perng
authors.initials: JP
authors.lastname: Chen
authors.forename: Jui-Ming
authors.initials: JM
authors.lastname: Sung
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Betty A
authors.initials: BA
authors.lastname: Wu-Hsieh
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Andrew
authors.initials: A
authors.lastname: Luster
authors.forename: Fang
authors.initials: F
authors.lastname: Liao
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003715:Dengue / Q000235:genetics / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D019562:Viral Load
chemical_list: D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D018836:Inflammation Mediators; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine