Dengue virus activates membrane TRAIL relocalization and IFN-a production by human plasmacytoid dendritic cells in vitro and in vivo

Dengue virus activates membrane TRAIL relocalization and IFN-a 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 dendr...

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Bibliographic Details
Published in:PLoS neglected tropical diseases Vol. 7; no. 6; pp. e2257 - e2271
Main Authors: Gandini, M., Gras, C., Azeredo E., Leal, Oliveira Pinto L.M., De, Smith, N., Despres, P., Cunha R.V., Da, Souza L.J., De, Kubelka, C., J.P., Herbeuval
Format: Journal Article
Language:English
Published: Public Library of Science 01-06-2013
Subjects:
Apoptosis
Cytokines
Dengue fever
Experiments
Flow cytometry
Immune system
Immunology
Ligands
Mortality
Patients
Plasma
Proteins
Viral infections
Young Adult
Dendritic Cells
Flow Cytometry
TNF-Related Apoptosis-Inducing Ligand
Interferon-alpha
Humans
Middle Aged
Adult
Female
Male
Dengue Virus
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Summary:  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 production Conclusions 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.
ISSN:1935-2727
1935-2735
DOI:10.1371/journal.pntd.0002257