Article
Dengue Virus Activates Membrane TRAIL Relocalization and IFN-a Production by Human Plasmacytoid Dendritic Cells In Vitro and In Vivo
Registro en:
GANDINI, Mariana; et al. Dengue Virus Activates Membrane TRAIL Relocalization and IFN-a Production by Human Plasmacytoid Dendritic Cells In Vitro and In Vivo. PLoS Negl Trop Dis, v.7, n.6, e2257, 14p, June 2013.
10.1371/journal.pntd.0002257
Autor
Gandini, Mariana
Gras, Christopher
Azeredo, Elzinandes Leal
Pinto, Luzia Maria de Oliveira
Smith, Nikaia
Despres, Philippe
Cunha, Rivaldo Venâncio da
Souza, Luiz José de
Kubelka, Claire Fernandes
Herbeuva, Jean-Philippe
Resumen
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-a 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-a 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-a 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-a treatment. Thus, pDC effect on viral load reduction was
mainly dependent on IFN-a 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.