title: Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells.
abstract: Dengue virus (DENV) is a re-emerging arthropod borne flavivirus that infects more than 300 million people worldwide, leading to 50,000 deaths annually. Because dendritic cells (DC) in the skin and blood are the first target cells for DENV, we sought to investigate the early molecular events involved in the host response to the virus in primary human monocyte-derived dendritic cells (Mo-DC). Using a genome-wide transcriptome analysis of DENV2-infected human Mo-DC, three major responses were identified within hours of infection - the activation of IRF3/7/STAT1 and NF-κB-driven antiviral and inflammatory networks, as well as the stimulation of an oxidative stress response that included the stimulation of an Nrf2-dependent antioxidant gene transcriptional program. DENV2 infection resulted in the intracellular accumulation of reactive oxygen species (ROS) that was dependent on NADPH-oxidase (NOX). A decrease in ROS levels through chemical or genetic inhibition of the NOX-complex dampened the innate immune responses to DENV infection and facilitated DENV replication; ROS were also essential in driving mitochondrial apoptosis in infected Mo-DC. In addition to stimulating innate immune responses to DENV, increased ROS led to the activation of bystander Mo-DC which up-regulated maturation/activation markers and were less susceptible to viral replication. We have identified a critical role for the transcription factor Nrf2 in limiting both antiviral and cell death responses to the virus by feedback modulation of oxidative stress. Silencing of Nrf2 by RNA interference increased DENV-associated immune and apoptotic responses. Taken together, these data demonstrate that the level of oxidative stress is critical to the control of both antiviral and apoptotic programs in DENV-infected human Mo-DC and highlight the importance of redox homeostasis in the outcome of DENV infection.
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Suraj
authors.initials: S
authors.lastname: Peri
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Steel
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Nadine
authors.initials: N
authors.lastname: van Montfoort
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiang
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Beljanski
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Slifker
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Zhong
authors.initials: Z
authors.lastname: He
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Carmen N
authors.initials: CN
authors.lastname: Nichols
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000473:pathology / Q000502:physiology* / Q000821:virology*; D003716:Dengue Virus / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D066298:In Vitro Techniques; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human