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.Dengue virus (DV) has reemerged as a major global health problem in the tropics, particularly among children (9, 26). This mosquito-borne flavivirus, for which there is no vaccine or antiviral treatment, causes an estimated 50 million infections annually (32, 34). Most DV infections result in a self-limited febrile illness (dengue fever). Less frequently, infections can cause dengue hemorrhagic fever, a potentially fatal plasma leakage syndrome.DV replication can be effectively controlled after a short period of viremia in most individuals. It is unclear, however, what host factors induced by DV infection are involved in regulating the virus. Increases in serum levels of type I and type II interferons (IFNs) have been observed during DV infection (21,22). Pretreatment of cells with type I IFN was shown to block DV infection of cells by a protein kinase receptor and 2Ј-5Ј oligoadenylate synthase (OAS)-independent mechanism (5), although it has been shown that DV infection inhibits type

CD8+T Cells Use TRAIL To Restrict West Nile Virus Pathogenesis by Controlling Infection in Neurons

“…We initiated this study because primary human cell culture experiments showed that TRAIL was induced after DENV infection and that treatment of human myeloid cells with exogenous, recombinant TRAIL inhibited DENV infection through an apoptosis-independent mechanism (40). To address the physiological function of TRAIL in vivo in the context of infection by a flavivirus, we assessed WNV pathogenesis in wild-type and TRAIL Ϫ/Ϫ mice.…”

“…Previous in vitro studies suggested that addition of high doses (e.g., 5 to 20 g/ml) of exogenous recombinant human TRAIL to cell cultures could inhibit infection with DENV, a related flavivirus (40). To assess directly the role of TRAIL in the context of WNV infection in vivo, we compared the survival rates of 8-to 9-week-old wild-type and congenic TRAIL Ϫ/Ϫ mice after subcutaneous infection with 10 2 PFU of a North American WNV isolate (New York, 2000).…”

“…However, they did not provide direct insight into the mechanism. We speculated that TRAIL might have a direct antiviral effect, as seen previously with the related flavivirus DENV (40). To address this possibility, we added increasing concentrations of recombinant TRAIL (0.078 to 20 g/ml) 1 day prior to WNV infection (MOI of 0.001) of primary cortical neurons in the absence of CD8 ϩ T cells.…”

Biomarcadores pronósticos de severidad del dengue

“…Yadav, et al, (22) en 1991, reportaron asociación entre los niveles de TNFα y el choque por dengue. Otro mediador de interés es el TRAIL, que regula la replicación de monocitos infectados con el virus del dengue, lo cual evidencia así su actividad antiviral (23). La liberación de TRAIL como respuesta a la infección por el el virus del dengue, hace parte importante de la respuesta inflamatoria que esta induce.…”

Análise transcricional de RNAs não codificadores longos em pacientes com dengue

“…A dengue grave em crianças causa um risco maior de choque enquanto que em adultos há um risco maior de hemorragias e danos aórgãos (SCREATON et al, 2015). (DEVIGNOT et al, 2010), (GOMES et al, 2010), (HOANG et al, 2010), (KWISSA et al, 2014a), (LOKE et al, 2010), (LONG et al, 2009), (SIMMONS et al, 2007, (UBOL et al, 2008), (WARKE et al, 2008), (NASCIMENTO et al, 2009), (SUN et al, 2013 NAKAYA et al, 2007).…”