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TRAIL Is a Novel Antiviral Protein against Dengue Virus

ABSTRACT: Dengue fever is an important tropical illness for which there is currently no virus-specific treatment. To shed light on mechanisms involved in the cellular response to dengue virus (DV), we assessed gene expression changes, using Affymetrix GeneChips (HG-U133A), of infected primary human cells and identified changes common to all cells. The common response genes included a set of 23 genes significantly induced upon DV infection of human umbilical vein endothelial cells (HUVECs), dendritic cells (DCs), monocytes, and B cells (analysis of variance, P < 0.05). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), one of the common response genes, was identified as a key link between type I and type II interferon response genes. We found that DV induces TRAIL expression in immune cells and HUVECs at the mRNA and protein levels. The induction of TRAIL expression by DV was found to be dependent on an intact type I interferon signaling pathway. A significant increase in DV RNA accumulation was observed in anti-TRAIL antibody-treated monocytes, B cells, and HUVECs, and, conversely, a decrease in DV RNA was seen in recombinant TRAIL-treated monocytes. Furthermore, recombinant TRAIL inhibited DV titers in DV-infected DCs by an apoptosis-independent mechanism. These data suggest that TRAIL plays an important role in the antiviral response to DV infection and is a candidate for antiviral interventions against DV. We used Affymetrix microarrays to study the response of human host cells to dengue virus (DV). Keywords: virus infection of multiple cell types

ORGANISM(S): Homo sapiens

PROVIDER: GSE9378 | GEO | 2008/01/05

SECONDARY ACCESSION(S): PRJNA103087

REPOSITORIES: GEO

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Project description:Dengue virus (DENV) infects hundreds of millions of people annually, yet there is only a limited knowledge of the host immune response to dengue. Here, we used a systems biological approach to perform a detailed analysis of the innate immune response to DENV infection in the whole blood samples of acutely infected humans in Bangkok, Thailand. Transcriptomic analysis revealed that genes encoding pro-inflammatory mediators and type I IFN related proteins, were associated with high levels of virus during the first few days of infection. Individuals with low or negative viremia at the late stage of fever were enriched with genes associated with pathways involved in cell cycle, proliferation, cell metabolism and translational control. Meta-analysis showed significant enrichment in genes specific for innate cells (monocytes, macrophages and DCs) in the specimens with high VL and enrichment in genes specific for NK cells, CD4+ and CD8+ T cells as well as B cells in specimens with low VL. Furthermore, flow cytometric analysis revealed an expansion in the numbers of CD14+CD16+ monocytes and depletion of CD14dimCD16++ cells and BDCA-1+ myeloid DC in blood. Consistent with this, in a non-human primate model, infection with DENV boosted the numbers of CD14+CD16+ monocytes in the blood and in secondary lymphoid organs. In vitro, freshly isolated blood monocytes infected with DENV up regulated CD16 and mediated robust differentiation of resting B cells to CD27++CD38++ plasmablasts and IgG and IgM secretion. Taken together, these data provide a detailed picture of the innate response to dengue infection in humans, and highlight an unappreciated role for CD14+CD16+ monocytes in promoting the differentiation of plasmablasts and mediating antibody response to DENV. We analyzed whole blood samples from 28 dengue patients (DF n=18, DHF=10) hospitalized at the Siriraj Hospital in Bangkok, Thailand during the season of 2009 The specimens were acquired between days 2 and 9 after onset of symptoms (acute illness), and for 19 patients (DF n=13, DHF=6) also at the convalescence at 4 weeks or later after discharge. Additionally, blood was sampled from 9 healthy, non-infected donors to provide controls for transcriptomic and immunological analysis.

Project description:Dengue is one of the most important arboviruses in the world, with 2.5 billion people living in areas under risk to contagious. Mosquitos from Aedes genus is the transmission vector of viral particles. The virus genome inserted in these particles is formed by a single strain of RNA molecule which codifies three structural (C, prM, and E proteins) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The NS3 protein is involved in viral replication, with helicase (NS3hell) and protease functions. Once inoculated, the primary target for dengue virus (DV) infection is the Dendritic Cells (DC) in the site of mosquitos bit. The Dendritic Cells is the most efficient antigen-presenting cell holding the connection of innate immune system with adaptive immune system. In this study we examined the response of human monocyte-derived DC (mdDCs) DV-infected with two different strains how contain a single point mutation in L435S or L480S position of NS3hell protein, named vBAC-NS3435 and vBAC-NS3480 respectively. The analysis of these results demonstrated that the mutated strains can infect more efficiently the mdDCs compared with parental virus (vBACDV1) with more percentage of cells infected, replication and virus progeny. Infections of mdDCs with mutated DV can induce a differentiated response in gene profile of theses cells, with up-regulation of IFN Signaling and PRR canonical pathways. In the PRR pathway the expression of TLR3 and TLR7 was determined and these seem to be the route of sensing of the ssRNA-virus for the infected mdDCs. These sensing of the DV by mdDCs is translated in production of Type I IFN. The Type I IFN production was more important in mdDC DV-infected with mutated strains compared with parental strain. However, the enhanced levels of Type I IFN production were unable to prevent mdDCs infection by mutated strains. A18:J192replication. In the absence of Type I IFN action, the percentage of mdDCs infected by mutated strains was significantly incremented compared with DV-infection in the presence of Type I IFN, demonstrating that the Type I IFN action was effective but not sufficient to prevent viral replication of mutated strains. The single point mutation in NS3hell protein of vBAC-NS3435 and vBAC-NS3480 are sufficient to enhance the replication and bypass the Type I IFN action. All these results together can demonstrated that the single point mutation in a NS3hel protein of DV can subvert the normal replication pathway of the virus and these change can’t by controlled by human mdDC production of Type I IFN.

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TRAIL Is a Novel Antiviral Protein against Dengue Virus

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