title: Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.
abstract: 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.affiliation: Department of Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Daniels
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Pinto
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Huang
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Vick
authors.affiliation: ZymoGenetics, a Bristol-Myers Squibb Company, Seattle, WA 98102, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Doyle
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. diamond@borcim.wustl.edu rklein@dom.wustl.edu.
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. diamond@borcim.wustl.edu rklein@dom.wustl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D017097:Electric Impedance; D005786:Gene Expression Regulation; D006801:Humans; D007111:Immunity, Cellular; D007372:Interferons / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D010539:Permeability; D018121:Receptors, Cytokine / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014779:Virus Replication; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus
chemical_list: D000998:Antiviral Agents; C579640:IFNLR1 protein, human; C000604340:IFNLR1 protein, mouse; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D011994:Recombinant Proteins; C000602567:interferon-lambda3, mouse; D007372:Interferons