Dataset Information

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells.

ABSTRACT: 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.

SUBMITTER: Lai JH

PROVIDER: S-EPMC6073071 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells.

Lai Jenn-Haung JH Wang Mei-Yi MY Huang Chuan-Yueh CY Wu Chien-Hsiang CH Hung Li-Feng LF Yang Chia-Ying CY Ke Po-Yuan PY Luo Shue-Fen SF Liu Shih-Jen SJ Ho Ling-Jun LJ

EMBO reports 20180607 8

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) ...[more]

PMID: 29880709

Similar Datasets

Project description:The dengue virus (DENV), transmitted by Aedes spp. mosquitoes, is one of the most important arboviral infections in the world. Dengue begins as a febrile condition, and in certain patients, it can evolve severe clinical outcomes, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The reasons why certain patients develop DHF or DSS have not been thoroughly elucidated to date, and both patient and viral factors have been implicated. Previous work has shown that a severe immune dysfunction involving dendritic cells and T cells plays a key role in increasing the disease severity, especially in secondary heterologous infections. Extracellular vesicles (EVs) are membranous particles that are secreted by several cell types involved in homeostatic and pathological processes. Secretion of EVs by infected cells can enhance immune responses or favor viral evasion. In this study, we compare the molecular content of EVs that are secreted by human primary dendritic cells under different conditions: uninfected or infected with DENV3 strains isolated from patients with different infection phenotypes (a severe case involving DSS and a mild case). Human monocyte-derived dendritic cells (mdDCs) were infected with the dengue virus strains DENV3 5532 (severe) or DENV3 290 (mild), and the EVs were isolated. The presence of cup-shaped EVs was confirmed by electron microscopy and immunostaining with CD9, CD81, and CD83. The RNA content from the mdDC-infected cells contained several mRNAs and miRNAs related to immune responses compared to the EVs from mock-infected mdDCs. A number of these RNAs were detected exclusively during infection with DENV3 290 or DENV3 5532. This result suggests that the differential immune modulation of mdDCs by dengue strains can be achieved through the EV pathway. Additionally, we observed an association of EVs with DENV-infectious particles that seem to be protected from antibodies targeting the DENV envelope protein. We also showed that EVs derived from cells treated with IFN alpha have a protective effect against DENV infection in other cells. These results suggested that during DENV infection, the EV pathway could be exploited to favor viral viability, although immune mechanisms to counteract viral infection can also involve DC-derived EVs.

Dataset Information

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells.

Publications

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets