title: Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway.
abstract: The Notch signalling pathway is involved in multiple cellular processes and has been recently indicated to modulate the host immune response. However, the role of the Notch pathway in dengue virus (DENV) infection remains unknown. Our study has screened the expression profile of Notch receptors, ligands and target genes in human monocytes, macrophages and dendritic cells in response to DENV infection. The real-time PCR data showed that Notch ligand Dll1 was significantly induced in DENV-infected monocytes; and receptor Notch4, ligands Dll1 and Dll4, and target Hes1 were dramatically enhanced in DENV-infected macrophages and dendritic cells. In macrophages, induction of Dll1 and Dll4 mediated by DENV2 was increased by treatment with interferon-β (IFN-β), and was impaired by neutralization of IFN-β. The DENV-induced Dll1 and Dll4 expression level was decreased by silencing key innate immune molecules, including Toll-like receptor 3 (TLR3), MyD88, RIG-I and IPS-I. In IFN-receptor-depleted macrophages, the Dll1 and Dll4 induction was significantly alleviated. Functionally, activation of Notch signalling by Dll1 in CD4(+) T cells enhanced the expression of a T helper type 1 (Th1) cytokine IFN-γ, while Notch activation in macrophages had no direct effect on replication of DENV. Our data revealed that the expressions of Notch ligands in antigen-presenting cells were differentially induced by DENV via innate immune signalling, which is important for Th1/Th2 differentiation during adaptive immune response.
authors.affiliation: Department of Immunology, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Diseases Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuye
authors.initials: Y
authors.lastname: Li
authors.forename: Siyu
authors.initials: S
authors.lastname: Wu
authors.forename: Jieying
authors.initials: J
authors.lastname: Pu
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D003715:Dengue / Q000276:immunology* / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008264:Macrophages / Q000382:microbiology* / Q000473:pathology; D008297:Male; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C573415:IFNG protein, human; D036341:Intercellular Signaling Peptides and Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D007371:Interferon-gamma
keywords: DENV; Dll1; Dll4; IFN-β