Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade

Abstract

Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30–50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

“…The expression levels of these two ISGs were used as surrogate markers for the induction of type I IFN, because we had previously observed that the level of expression of type I IFNs in the LCMV-infected CNS borders on the level of detection (8); this approach is validated by our observation that there is no virus-induced increase in the expression of either of these genes in LCMV-infected IFNAR Ϫ/Ϫ mice (8).…”

“…A key factor in this recruitment seems to be the local production of the chemokine CXCL10, which interacts with the chemokine receptor CXCR3 on the activated CD8 T cells (6,7). Upon contact between incoming CD8 T cells and virus-infected cells in different parts of the CNS, large amounts of type II IFN are released, further increasing the local production of important chemoattractants, including CXCL10 (8). The whole process culminates in a severe CD8 ϩ T-cell-mediated inflammatory reaction in essential parts of the CNS, cerebral edema, and death 7 to 9 days after virus inoculation (8,35).…”

“…The whole process culminates in a severe CD8 ϩ T-cell-mediated inflammatory reaction in essential parts of the CNS, cerebral edema, and death 7 to 9 days after virus inoculation (8,35). Using IFNARdeficient (IFNAR Ϫ/Ϫ ) mice, we have previously shown that type I IFNs are essential in activating certain aspects of the local antiviral host response, including the early production of CXCL10 (8). However, it is not known how the early type I IFN response is regulated within the LCMV-infected CNS, nor has the cellular source(s) been described.…”

“…Upon contact between incoming CD8 T cells and virus-infected cells in different parts of the CNS, large amounts of type II IFN are released, further increasing the local production of important chemoattractants, including CXCL10 (8). The whole process culminates in a severe CD8 ϩ T-cell-mediated inflammatory reaction in essential parts of the CNS, cerebral edema, and death 7 to 9 days after virus inoculation (8,35). Using IFNARdeficient (IFNAR Ϫ/Ϫ ) mice, we have previously shown that type I IFNs are essential in activating certain aspects of the local antiviral host response, including the early production of CXCL10 (8).…”

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

“…CXCL10 has been reported to play an important role in host defense following a variety of viral infections. Using CXCL10 2/2 mice, the major function for CXCL10 in host defense against viral infection has been shown to be recruitment of effector T cells and NK cells to sites of infection/inflammation (19)(20)(21)(22)(23)(24)(25). However, CXCL10 function specific to DENV infection has not been examined in vivo.…”