title: Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration.
abstract: Type I IFNs, which include IFN-alpha, 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-alpha1 chronically from astrocytes. These glial fibrillary acidic protein-IFN-alpha 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-alpha. Our data suggest that IFN-alpha overproduction may be the primary factor initiating these human diseases. Following intracerebral infection with lymphocytic choriomeningitis virus, glial fibrillary acidic protein-IFN-alpha 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-alpha 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.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Akwa
authors.forename: D E
authors.initials: DE
authors.lastname: Hassett
authors.forename: M L
authors.initials: ML
authors.lastname: Eloranta
authors.forename: K
authors.initials: K
authors.lastname: Sandberg
authors.forename: E
authors.initials: E
authors.lastname: Masliah
authors.forename: H
authors.initials: H
authors.lastname: Powell
authors.forename: J L
authors.initials: JL
authors.lastname: Whitton
authors.forename: F E
authors.initials: FE
authors.lastname: Bloom
authors.forename: I L
authors.initials: IL
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002114:Calcinosis / Q000209:etiology; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D005911:Gliosis / Q000209:etiology; D016898:Interferon-alpha / Q000009:adverse effects / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008216:Lymphocytic Choriomeningitis / Q000517:prevention & control*; D008590:Meningoencephalitis / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019076:Transgenes; D019562:Viral Load
chemical_list: D005904:Glial Fibrillary Acidic Protein; D016898:Interferon-alpha; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins