TRANSGENIC EXPRESSION OF IFN-ALPHA IN THE CENTRAL-NERVOUS-SYSTEM OF MICE PROTECTS AGAINST LETHAL NEUROTROPIC VIRAL-INFECTION BUT INDUCES INFLAMMATION AND NEURODEGENERATION

Type I IFNs, which include IFN-alpha, appear to have complex and broad -ranging actions in the central nervous system (CNS) that may result i n protection or injury. To better understand these issues, we generate d transgenic mice that produce IFN-alpha, chronically from astrocytes, These glial fibrillary acidic protein-IFN-alpha transgenic mice devel oped a progressive inflammatory encephalopathy, with marked calcium mi neralization, meninoencephalitis, gliosis, and neurodegeneration. Many features of this murine encephalopathy resembled those found in certa in human encephalopathies of unknown etiology; these diseases, exempli fied by Aicardi-Goutieres syndrome and some viral encephalopathies, sh ow increased intrathecal production of IFN-alpha, Our data suggest tha t IFN-alpha overproduction may be the primary factor initiating these human diseases. Following intracerebral infection with Iymphocytic cho riomeningitis virus, glial fibrillary acidic protein-IFN-alpha mice ha d significantly increased survival rates associated with markedly redu ced virus titers and immune pathology in the brain but normal peripher al CTL responses. Therefore, the production of IFN-alpha in the CNS ca n be a two-edged sword that on the one hand confers protection against a lethal viral infection but on the other causes significant injury t o the brain. These transgenic mice provide a novel animal model in whi ch to further evaluate the mechanisms that underlie the diverse action s of type I IFNs in the intact CNS.