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  • Infection with the dengue R...
    Lai, Jenn‐Haung; Wang, Mei‐Yi; Huang, Chuan‐Yueh; Wu, Chien‐Hsiang; Hung, Li‐Feng; Yang, Chia‐Ying; Ke, Po‐Yuan; Luo, Shue‐Fen; Liu, Shih‐Jen; Ho, Ling‐Jun

    EMBO reports, August 2018, Letnik: 19, Številka: 8
    Journal Article

    Toll‐like receptors (TLRs) are important sensors that recognize pathogen‐associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV‐induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side‐by‐side comparison of TLR9 and cyclic GMP‐AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV‐induced immune activation. The significance of TLR9 in DENV‐induced immune response is also confirmed in examination with the bone marrow‐derived DCs prepared from Tlr9‐knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs. Synopsis Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol. Infection of human DCs with DENV induces ROS generation, inflammasome activation, oxidization of mtDNA and opening of the mitochondrial permeability transition pores resulting in the release of both non‐oxidized and oxidized mtDNA into the cytosol. Cytosolic mtDNA increases TLR9 expression, binds to TLR9 and induces immune activation such as anti‐viral interferon production. The significance of TLR9 in DENV infection is confirmed by examining bone marrow‐derived dendritic cells prepared from Tlr9‐knockout mice. Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol.