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-γ, and CXCL11/IFN-inducible T cell α 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.

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

“…NT_109320, NW_001030791, NT_039339), our analyses would indicate that CXCL10 is the relevant CXCR3 ligand expressed in the CNS during WNV encephalitis in these animals. These results agree with recent studies examining intracranial inoculation with lymphocytic choriomeningtis virus (LCMV) or dengue virus in which both CXCL10 and CXCR3 were determined to be required for the migration of virus-specific, effector T cells into LCMVinfected meninges and into dengue-infected brains (57)(58)(59). Additionally, nonredundant roles for these two chemokines were recently demonstrated in a model of HSV-1 corneal infection in which CXCL9 alone was required for CD4 T cell infiltration into this tissue site (60).…”

Spectrum of disease outcomes in mice infected with YFV-17D

“…Interestingly, IP-10 was the only chemokine significantly induced in YFV-17D-vaccinated individuals (Querec et al, 2009), suggesting an important role for YFV-17D immunogenicity in healthy humans with intact immune responses. It has also been shown that IP-10 contributes to decreased DENV replication in immune-deficient IFN regulatory factor (IRF)-3/ IRF-7 knockout mice (Chen et al, 2013) and IP-10 reduces neurological disease in WNV-or DENV-infected mice (Hsieh et al, 2006;Klein et al, 2005). These findings suggest that chemokines and cytokines such as IP-10 play an important role in the balance between pathogen control and immunopathology, and these proteins may have different activity in neuronal versus non-neuronal tissues.…”

Unaltered Neurological Disease and Mortality in CXCR3-Deficient Mice Infected Intracranially with Lymphocytic Choriomeningitis Virus-Armstrong

“…While these chemokines are not detectable in the healthy brain, their expression is highly upregulated following infection of the CNS with various viruses (2,3,10,21,23,24). Deficiency of CXCR3 has been associated with reduced trafficking to and/or positioning of T cells in the CNS in a number of different virally-induced disease models, such as West Nile virus encephalitis (45), mouse hepatitis virus encephalitis (43), and dengue virus encephalitis (18).…”