Chemokine Gene Expression in Astrocytes of Borna Disease Virus-Infected Rats and Mice in the Absence of Inflammation

Abstract

Borna disease virus (BDV) causes CD8؉ T-cell-mediated meningoencephalitis in immunocompetent mice and rats, thus providing a valuable animal model for studying the mechanisms of virus-induced central nervous system (CNS) immunopathology. Chemokine-mediated leukocyte recruitment to the CNS is a crucial step in the development of neurological disease. We found increased mRNA levels of IP-10 and other chemokines in brains of adult rats following infection with BDV. The marked increase in chemokine gene expression at about day 8 postinfection seemed to immediately precede the inflammatory process. In brains of rats infected as newborns, in which inflammation was only mild and transient, sustained expression of IP-10 and RANTES genes was observed. In situ hybridization studies revealed that astrocytes were the major source of IP-10 mRNAs in brains of rats infected as newborns and as adults. In brains of infected mice lacking CD8 ؉ T cells (␤2m 0/0 ), transcripts encoding IP-10 and RANTES were also observed. IP-10 transcripts were also present in a small number of scattered astrocytes of infected knockout mice lacking mature B and T cells as well as functional alpha/beta and gamma interferon receptors, indicating that BDV can induce chemokine synthesis in the absence of interferons and other B-or T-cell-derived cytokines. These data provide strong evidence that CNS-resident cells are involved in the early localized host immune response to infection with BDV and support the concept that chemokines are pivotal for the initiation of virus-induced CNS inflammation.

Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

“…2F) were immunoreactive for BDV-N. Neural, chemokine, and cytokine genes are almost unaltered in infected slice cultures. Cerebral BDV infection of mice and rats can induce chemokine expression in astrocytes in the absence of infiltrating leukocytes (19). Therefore, a number of different RPA probe sets were utilized to determine whether BDV infection leads to altered expression of neural, chemokine, and cytokine genes in 18-day-old cerebellar slice cultures ( Fig.…”

The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

“…7) (30). Rather, we expect that the enhanced permeability facilitates the invasion of cells both physically and by promoting contact with chemoattractive factors, such as chemokines, which are expressed in the BDVinfected rat brain in the absence of inflammation (41).…”

The functional avidity of virus‐specific CD8+ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

“…Alternatively, sustained exposure of T cells to cytokines or other factors in the CNS might induce TCR downmodulation. Prolonged exposure of T cell hybridomas to tumor necrosis factor-a, which is strongly up-regulated in BDV-infected mouse brains [30], has been shown to reversibly reduce TCR surface expression and increase the peptide concentration required to stimulate IL-2 production [31]. However, a significant fraction of TCR int cells also showed a marked elevation of tetramer binding after overnight cultivation.…”