Impaired microglial activation in the brain of IL-18-gene-disrupted mice after neurovirulent influenza A virus infection

Abstract

Knockout of the inerleukin-18 (IL-18) gene predisposed mice to impaired clearance of neurovirulent influenza A virus-infected neurons from the brain. In wild-type mice, IL-18 molecule-producing microglia/macrophages emerged in vitally attacked regions as early as day 3 after infection. Microglial transformation into macrophages culminated at day 7 to 9, with upregulated expression of Iba1, a novel calcium-binding protein that controls phagocytic functions of microglia/macro-phages. In IL-18-/- mice, microglial transformation was interrupted with reduced Iba1 expression. Interferon-γ (IFN-γ)-immunopositive neurons appeared in and around vitally invaded regions in wild-type mice, peaking in number at day 7, whereas such cells were barely detected in IL-18-/- mice. Stereotaxic microinjection of recombinant IFN-γ triggered microglial transformation in IL-18-/- mice and upregulated Iba1 expression, leading to effective eradication of vitally infected neurons. Collectively, these results suggest that IL-18 plays a key role in activating microglial functions directed against the influenza virus infection by inducing neuronal IFN-γ in the brain parenchyma. © 2001 Academic Press.