Chemokine Expression in the Central Nervous System of Mice with a Viral Disease Resembling Multiple Sclerosis: Roles of CD4⁺and CD8⁺T Cells and Viral Persistence

Abstract

During the first 45 days after intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV), the levels of mRNAs encoding chemokines MCP-1/CCL2, RANTES/CCL5, and IP-10/CXCL10 in the central nervous system (CNS) are closely related to the sites of virus gene expression and tissue inflammation. In the present study, these chemokines were monitored during the latter 135 days of a 6-month course of TMEVinduced disease in susceptible (PLJ) or resistant (C57BL/6) mice that possessed or lacked either CD4 ؉ or CD8 ؉ T cells. These data were additionally correlated to mouse genotype, virus persistence in the CNS, antiviral antibody titers, mortality, and the severity of neurological disease. Surprisingly, the major determinant of chemokine expression was virus persistence: the factors of susceptible or resistant genotype, severity of neuropathology, and presence or absence of regulatory T cells exerted minimal effects. Our observations indicated that chemokine expression in the CNS in this chronic viral disorder was intrinsic to the CNS innate immune response to infection and was not governed by elements of the adaptive immune system.Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) causes poliomyelitis that is rapidly cleared in susceptible and resistant mouse strains but is succeeded by viral persistence and inflammatory demyelination in susceptible strains of mice (7,19,21,31,33). By thorough analysis of congenic strains, the determinants of susceptibility have been mapped to both major histocompatibility complex (MHC) and non-MHC genes (19). This genetic analysis has been extended by studying TMEV disease in genetargeted mice. Recent results revealed that both CD4 and CD8 cells were required to control infection (16). CD4 ϩ cells additionally provided protection against neurological deficits that result from inflammatory demyelination (16,28).Chemokines constitute a family of peptides that act through specific high-affinity receptors (3). In concert with adhesion molecules, they define both physiological and pathological leukocyte migration patterns (5). Expression of chemokines has been defined for early time points after TMEV infection but not in chronic disease (15). Further, the regulation of TMEVinduced chemokine expression in CD4-and CD8-deficient mice has not been addressed. We used real-time reverse transcriptase PCR (RT-PCR) to evaluate CNS chemokine expression in susceptible and resistant mice, with or without deletion of CD4 or CD8 genes, across a 6-month time course of disease. These data were correlated with viral persistence, clinical deficits, mortality, and serum-neutralizing antiviral antibodies.These analyses allowed us to determine how quantitative or qualitative CNS chemokine expression was determined by the presence or absence of CD4 ϩ or CD8 ϩ T cells by susceptible or resistant genotype or by persistent viral replication. We found that quantitative and qualitative aspects of CNS chemokine expression in TMEV-infected mice were not consi...

Transition from Acute to Persistent Theiler's Virus Infection Requires Active Viral Replication That Drives Proinflammatory Cytokine Expression and Chronic Demyelinating Disease

“…3). Previously, chemokine expression was reported to be low in resistant C57BL/10 and B6 cords after the acute phase of infection (34,42), and the B6 spinal cords were therefore not assayed for this study. Thus, an increase in chemokine expression was not observed in SJL/J cords during the transition to persistent infection, as was seen with cytokine expression.…”

“…Chemokines are soluble, activation-inducible, proinflammatory molecules that are chemotactic for different cell types and are up-regulated during TMEV infection (21,34,42). RNase protection assays were performed to determine the expression levels of chemokine mRNAs during BeAn infections of SJL/J and B6 mice.…”

“…Recently, Ransohoff et al (42) reported that TMEV persistence (measured in infectious virus titers) is the major determinant for chronic chemokine expression in wild-type as well as CD4…”

Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus

“…Chemokines are the principal chemotactic factors that mediate leukocyte migration to sites of inflammation and/or infection (17,18). Among these, the IFN-␥-inducible CXC chemokines, CXCL10/IFN-inducible protein 10 (IP-10), 4 CXCL9/ monokine induced by IFN-␥ (Mig), and CXCL11/IFN-inducible T cell ␣ chemoattractant (I-TAC), mainly attract effector T cells and NK cells that express the receptor CXCR3 (19,20), and several studies have shown that viral infection leads to up-regulation of their expression (21)(22)(23)(24)(25). Of these chemokines, CXCL10/IP-10 has been the most widely studied in the context of mouse models of CNS infection (22,23), and has been shown to play a key role in the trafficking and recruitment of effector T cells (26).…”

CXCL10 Production from Cytomegalovirus-Stimulated Microglia Is Regulated by both Human and Viral Interleukin-10

“…Both astrocytes and microglial cells respond to various antigenic stimuli to produce CXCL10 (18,66). Astrocytes produce CXCL10 in response to IFN-␥, TNF-␣ (42,49), and viral proteins like human immunodeficiency virus type 1 gp120 (4) and during viral infections (10,50,53,54,58). Microglial cells and other cells of the monocyte/macrophage lineage also produce CXCL10 in response to bacterial lipopolysaccharide (LPS) (26) and IFN-␥ (66).…”