IFN-γ Is Not Required in the IL-12 Response to Vesicular Stomatitis Virus Infection of the Olfactory Bulb

In this report, the role of IFN-γ in host defense to exogenous IL-12 and clearance of vesicular stomatitis virus (VSV) from the central nervous system was examined. Wild-type and IFN-γ knockout mice infected with VSV were treated with IL-12 or medium. In both groups, IL-12 treatment resulted in 1) substantially decreased VSV titers in brain homogenates and diminished immunohistochemical detection of VSV Ags in tissue sections; 2) induction of types 1, 2, and 3 nitric oxide synthase; and 3) induction of MHC molecules and rapid infiltration of both T cells and NK cells. These results suggest that IFN-γ production, both systemically and in the olfactory bulb, contributes to but is not essential for clearance of VSV from the brain. Neutralization of TNF-α in IFN-γ knockout mice mice treated with IL-12 was accompanied by the same immunohistochemical changes, implying that neither IFN-γ nor TNF-α was required. In vitro studies using purified IL-12 or IFN-γ in culture medium induced nitric oxide synthase isoforms in neurons, glia, and macrophages, and MHC II on glia and macrophages. These data suggest that IL-12 directly activates neurons to promote viral clearance in vivo.