Dengue Virus Activates Membrane TRAIL Relocalization and IFN-α Production by Human Plasmacytoid Dendritic Cells in Vitro and in Vivo

Background:dengue displays a broad spectrum of clinical manifestations that may vary from asymptomatic to severe and even fatal features. plasma leakage/hemorrhages can be caused by a cytokine storm induced by monocytes and dendritic cells during dengue virus (denv) replication. plasmacytoid dendritic cells (pdcs) are innate immune cells and in response to virus exposure secrete ifn-α and express membrane trail (mtrail). we aimed to characterize pdc activation in dengue patients and their function under denv-2 stimulation in vitro.methods & findings:flow cytometry analysis (fca) revealed that pdcs of mild dengue patients exhibit significantly higher frequencies of mtrail compared to severe cases or healthy controls. plasma levels of ifn-α and soluble trail are increased in mild compared to severe dengue patients,positively correlating with pdc activation. fca experiments showed that in vitro exposure to denv-2 induced mtrail expression on pdc. furthermore,three dimension microscopy highlighted that trail was relocalized from intracellular compartment to plasma membrane. chloroquine treatment inhibited denv-2-induced mtrail relocalization and ifn-α production by pdc. endosomal viral degradation blockade by chloroquine allowed viral antigens detection inside pdcs. all those data are in favor of endocytosis pathway activation by denv-2 in pdc. coculture of pdc/denv-2-infected monocytes revealed a dramatic decrease of antigen detection by fca. this viral antigens reduction in monocytes was also observed after exogenous ifn-α treatment. thus,pdc effect on viral load reduction was mainly dependent on ifn-α productionconclusions:this investigation characterizes,during denv-2 infection,activation of pdcs in vivo and their antiviral role in vitro. thus,we propose trail-expressing pdcs may have an important role in the outcome of disease. © 2013 gandini et al.