Cellular Oxidative Stress Response Controls the Antiviral and Apoptotic Programs in Dengue Virus-Infected Dendritic Cells

• DOI: 10.1371/journal.ppat.1004566
• Publication Date: 2014-12-19T08:11:27Z
• Authors: David Olagnier; Suraj Peri; Courtney Steel; Nadine van Montfoort; Cindy Chiang; Vladimir Beljanski; Michael Slifker; Zhong He; Carmen N. Nichols; Rongtuan Lin; Siddharth Balacha...; John Hiscott
• Keywords: 570; QH301-705.5; NF-E2-Related Factor 2; Cells; 610; Apoptosis; In Vitro Techniques; Virus Replication; 03 medical and health sciences; Medical Specialties; Medicine and Health Sciences; Innate; Humans; Biology (General); Cells, Cultured; 0303 health sciences; Cultured; Gene Expression Profiling; Immunity; NF-kappa B; Dendritic Cells; Experimental Medicine; RC581-607; Dengue Virus; Immunity, Innate; 620; 3. Good health; Oxidative Stress; Osteopathic Medicine and Osteopathy; STAT1 Transcription Factor; Interferon Regulatory Factor-3; Immunologic diseases. Allergy; Reactive Oxygen Species; Research Article

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 first target for DENV, we sought investigate early molecular events involved host response primary human monocyte-derived (Mo-DC). Using genome-wide transcriptome analysis of DENV2-infected Mo-DC, three major responses were identified within hours infection - activation IRF3/7/STAT1 NF-κB-driven antiviral inflammatory networks, as well stimulation an oxidative stress included Nrf2-dependent antioxidant gene transcriptional program. DENV2 resulted intracellular accumulation reactive oxygen species (ROS) was dependent on NADPH-oxidase (NOX). A decrease ROS levels through chemical or genetic inhibition NOX-complex dampened innate immune DENV facilitated replication; also essential driving mitochondrial apoptosis infected Mo-DC. In addition stimulating increased led bystander Mo-DC which up-regulated maturation/activation markers less susceptible viral replication. We have critical role transcription factor Nrf2 limiting both cell death by feedback modulation stress. Silencing RNA interference DENV-associated apoptotic responses. Taken together, these data demonstrate level control programs DENV-infected highlight importance redox homeostasis outcome infection.