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.
Highlights
Dengue virus (DENV) is the leading arthropod-borne viral infection in the world, and represents a major global human health concern
Primary CD14+ CD1a2 monocytes were less permissive to DENV2 infection, whereas infectivity increased progressively as the cells differentiated toward the Mo-dendritic cells (DC) (CD142 CD1a+) phenotype (4.6660.45% of DENV+ cells in monocytes at day 0 vs 79.660.47% in monocytederived dendritic cells (Mo-DC) at day 7) (Fig. 1A)
To uncover novel regulatory pathways involved in DENV infection of Mo-DC, we have for the first time used a transcriptome-wide expression analysis, coupled with biochemical dissection, to investigate the early host response to DENV infection in primary human dendritic cells - an important pool of cells infected early in vivo after the bite of the mosquito Aedes aegypti
Summary
Dengue virus (DENV) is the leading arthropod-borne viral infection in the world, and represents a major global human health concern. Of the estimated 50– 100 million annual cases, the majority of infected individuals develop a self-limiting febrile illness, but approximately 500,000 clinical cases result in more severe manifestations, such as DENVinduced hemorrhagic fever and shock syndrome [1], leading to 25–50,000 deaths per year [4]. TLR3 and TLR7 recognize DENV RNA and mount a rapid protective immune response in human monocytic cells and plasmacytoid dendritic cells, respectively [11,12].
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