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in the Central Nervous System of Mice Protects Against Lethal Neurotropic Viral Infection but Induces Inflammation and Neurodegeneration1
*
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037;
Department of Veterinary Microbiology, Division of Immunology, Swedish University of Agricultural Sciences, Uppsala, Sweden;
Astra Arcus AB, Sodertälje, Sweden; and
§
Department of Pathology, University of San Diego, San Diego, CA 92093
Type I IFNs, which include IFN-
, appear to have complex and
broad-ranging actions in the central nervous system (CNS) that may
result in protection or injury. To better understand these issues, we
generated transgenic mice that produce IFN-1 chronically
from astrocytes. These glial fibrillary acidic protein-IFN-
transgenic mice developed a progressive inflammatory encephalopathy,
with marked calcium mineralization, meninoencephalitis, gliosis, and
neurodegeneration. Many features of this murine encephalopathy
resembled those found in certain human encephalopathies of unknown
etiology; these diseases, exemplified by Aicardi-Goutières
syndrome and some viral encephalopathies, show increased intrathecal
production of IFN-. Our data suggest that IFN- overproduction may
be the primary factor initiating these human diseases. Following
intracerebral infection with lymphocytic choriomeningitis virus, glial
fibrillary acidic protein-IFN- mice had significantly increased
survival rates associated with markedly reduced virus titers and immune
pathology in the brain but normal peripheral CTL responses. Therefore,
the production of IFN- in the CNS can be a two-edged sword that on
the one hand confers protection against a lethal viral infection but on
the other causes significant injury to the brain. These transgenic mice
provide a novel animal model in which to further evaluate the
mechanisms that underlie the diverse actions of type I IFNs in the
intact CNS.
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