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.
Highlights
Dengue virus (DENV) is a positive-strand RNA virus belonging to Flaviviridae family of viruses
The results demonstrate that dengue virus (DENV) infection preferentially induced production of IFN-λ 1 in dendritic cells (DCs) and the human lung epithelial cell line A549 via its nonstructural 1 (NS1) glycoprotein
DENV infection induced expression of IFN-λ 1, IFN-λ 2, IFN-λ 3 and IFN-β 1 mRNA in DCs (Fig. 1A,B)
Summary
Dengue virus (DENV) is a positive-strand RNA virus belonging to Flaviviridae family of viruses. IFN-λ binds to a receptor complex containing two subunits, IFN-λ receptor 1 (IFN-λ R1) and interleukin (IL)-10R2, and, like type I IFNs, mediates antiviral activity through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and induction of IFN-stimulated genes (ISGs). Genome-wide association studies (GWASs) identified that both IFN-λ3 and IFN-λ4 genes were linked to clearance of viruses such as hepatitis C virus, human cytomegalovirus and herpes simplex virus 17,14,15. The focused nature of IFN-λ –mediated signaling pathways suggests that IFN-λ is less likely to result in the adverse events associated with the clinical use of IFN-α /β 14,16. In addition to DCs, the human lung epithelial cell line A549 has long been adopted for studying the effects and mechanisms of DENV infection, especially in investigations of the effects of IFNs19,20. Because the role of IFN-λ in DENV infection remains largely unknown, we investigated how DENV regulates IFN-λ production and the effects of IFN-λ in human DCs
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