Interferon lambda restricts West Nile virus neuroinvasion by enhancing integrity of the blood-brain barrier

Although type III interferons (IFN), also known as IFN-? or IL28/IL-29, restrict infection by several viruses, their mechanism of inhibitory action has remained uncertain. We used recombinant IFN-? and mice lacking the IFN-? receptor (IFNLR1) to evaluate the effect of IFN-? on infection with West Nile virus (WNV), an encephalitic flavivirus. Cell culture studies in keratinocytes and dendritic cells showed no direct antiviral effect of exogenous IFN-? even though ISGs were induced. Correspondingly, we observed no differences in WNV burden between wild-type and Ifnlr1-/- mice in the draining lymph node, spleen, and blood. However, we detected earlier dissemination and increased WNV infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect on infection of neurons. Instead, an increase in blood-brain barrier (BBB) permeability was observed in Ifnlr1-/- mice. Accordingly, treatment of mice with pegylated IFN-?2 resulted in decreased BBB permeability, reduced WNV infection in the brain without impacting viremia, and improved survival against lethal virus challenge. An in vitro model of the BBB showed that IFN-? signaling in brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and STAT1-independent manner. Our data establish a novel indirect antiviral function of IFN-? in which non-canonical signaling through IFNLR1 tightens the BBB and restricts viral neuroinvasion and pathogenesis. This finding suggests new clinical applications for IFN-? in treating viral or autoimmune diseases. Overall design: Transcriptome profiling of bone-marrow derived Dendritic cells(BMDCs), treated with either Serum Free Media(Mock), interferon beta(IFNb), or interferon lambda(IFNL) for 6 hours.

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Lazear HM, Daniels BP, Pinto AK, Huang AC, Vick SC, Doyle SE, Gale M Jr, Klein RS, Diamond MS