title: Dengue virus infection induces interferon-lambda1 to facilitate cell migration.
abstract: A marked increase in the rate of dengue virus (DENV) infection has resulted in more than 212 deaths in Taiwan since the beginning of 2015, mostly from fatal outcomes such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms of these fatal manifestations are poorly understood. Cytokines induce an overwhelming immune reaction and thus have crucial roles. Interferon-lambda (IFN-λ), a newly identified IFN subtype, has antiviral effects, but its immunologic effects in DENV infection have not been investigated. In the present study, we show that DENV infection preferentially induced production of IFN-λ1 in human dendritic cells (DCs) and human lung epithelial cells. Virus nonstructural 1 (NS1) glycoprotein was responsible for the effect. DENV-induced production of IFN-λ1 was dependent on signaling pathways involving toll-like receptor (TLR)-3, interferon regulation factor (IRF)-3, and nuclear factor-kappaB (NF-κB). Blocking interaction between IFN-λ1 and its receptor IFN-λR1 through siRNA interference reduced DENV-induced DC migration towards the chemoattractants CCL19 and CCL21, by inhibiting CCR7 expression. Furthermore, IFN-λ1 itself induced CCR7 expression and DC migration. Our study presents the first evidence of the mechanisms and effects of IFN-λ1 induction in DENV-infected DCs and highlights the role of this cytokine in the immunopathogenesis of DENV infection.
authors.affiliation: Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan, R.O.C.
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Wang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, R.O.C.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Ho
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan, R.O.C.|Graduate Institute of Clinical Research, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Jenn-Haung
authors.initials: JH
authors.lastname: Lai
mesh_terms: D000072283:A549 Cells; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000494:pharmacology; D054421:Chemokine CCL21 / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D003715:Dengue / Q000276:immunology / Q000473:pathology / Q000821:virology*; D003716:Dengue Virus / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D054400:Receptors, CCR7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D054415:Chemokine CCL19; D054421:Chemokine CCL21; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D016328:NF-kappa B; D009570:Nitriles; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D011994:Recombinant Proteins; D013450:Sulfones; D051196:Toll-Like Receptor 3; D017361:Viral Nonstructural Proteins; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C000624353:interferon-lambda, human; D007378:Interleukins; D000095022:Interferon Lambda