Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

• Published in: Science translational medicine 2015-04, Vol.7 (284), p.284ra59-284ra59
• Main Authors: Lazear, Helen M, Daniels, Brian P, Pinto, Amelia K, Huang, Albert C, Vick, Sarah C, Doyle, Sean E, Gale, Jr, Michael, Klein, Robyn S, Diamond, Michael S
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Antiviral Agents - chemistry; Blood-Brain Barrier; Brain - metabolism; Cell Line; Electric Impedance; Gene Expression Regulation; Humans; Immunity, Cellular; Interferons - pharmacology; Keratinocytes - cytology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Microscopy, Confocal; Neurons - metabolism; Neurons - virology; Permeability; Receptors, Cytokine - metabolism; Receptors, Interferon - metabolism; Recombinant Proteins - pharmacology; Signal Transduction; Virus Replication; West Nile Fever - immunology; West Nile Fever - pathology; West Nile virus
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aaa4304

Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse 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 signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.