title: Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery.
abstract: Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-β, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.
authors.affiliation: 1 Division of Allergy, Immunology, and Rheumatology, Kaohsiung Veterans General Hospital , Kaohsiung, Taiwan .
authors.forename: Li-Fong
authors.initials: LF
authors.lastname: Wang
authors.forename: You-Sheng
authors.initials: YS
authors.lastname: Lin
authors.forename: Nan-Chieh
authors.initials: NC
authors.lastname: Huang
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Yu
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Tsai
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Siang-Ru
authors.initials: SR
authors.lastname: Chen
authors.forename: Chih-Shiang
authors.initials: CS
authors.lastname: Yang
authors.forename: Ruo-Wei
authors.initials: RW
authors.lastname: Lu
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000276:immunology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D006886:Hydroxychloroquine; D007372:Interferons