Neurotropic coronavirus induces acute encephalomyelitis and demyelination in mice. Infection of BALB/c (H-2d) mice expressing a dominant negative gamma interferon (IFN-ฮณ) receptor specifically in oligodendrocytes was examined to determine the influence of IFN-ฮณ signaling on pathogenesis. Inhibition of IFN-ฮณ signaling in oligodendrocytes increased viral load, infection of oligodendrocytes, oligodendrocyte loss, demyelination, and axonal damage resulting in increased mortality. IFN-ฮณ levels and the inflammatory response were not altered, although the level of tumor necrosis factor (TNF) mRNA was increased. These data indicate that IFN-ฮณ signaling by oligodendroglia reduces viral replication but affects both demyelination and tissue destruction in a host-specific manner. Copyright ยฉ 2010, American Society for Microbiology.