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

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Abstract
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-/-. Il1r1-/- mice had lower survival, higher disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokines and chemokines than control C57BL/6 mice. We also examined infections of mice defective in IL-1β production (Pycard-/-mice) and mice defective in trafficking of TLRs to the endosome (Unc93b1-/- mice). Pycard-/- and Unc93b1-/- mice had 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 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 - 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.
Funding Information
  • NIH NIAID (R01 AI23762)
  • NIH NIAID (R01 091721)
  • Brazil Science Without Borders (2548/13-5)
  • NIH NCI (P30CA046592)