A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis.

UNLABELLED

Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 mice). Il1r1 mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 mice). Pycard and Unc93b1 mice showed lower survival (similar to Il1r1 mice) than control mice but, unlike Il1r1 mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 mice had a very different inflammatory profile from infected Il1r1 and Pycard mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 mice. A time course of infection of control and Il1r1 mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation.

IMPORTANCE

The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.