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DENGUE VIRUS ACTIVATES MEMBRANE TRAIL RELOCALIZATION AND IFN-A PRODUCTION BY HUMAN PLASMACYTOID DENDRITIC CELLS IN VITRO AND IN VIVO
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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Université Paris Descartes. CNRS UMR 8147. Paris, Frrance.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Université Paris Descartes. CNRS UMR 8601. Chimie et Biologie, Nucléo(s)tides et Immunologie Thérapeutique (CBNIT). Paris, France.
Institut Pasteur. Unité des Interactions moléculaires Flavivirus-Hôtes. Paris, France
Universidade Federal do Mato Grosso do Sul. Faculdade de Medicina. Departamento de Clínica Medica. Campo Grande, MS, Brasil.
Centro de Referencia em Dengue.Campos de Goytacases, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Université Paris Descartes. CNRS UMR 8601. Chimie et Biologie, Nucléo(s)tides et Immunologie Thérapeutique (CBNIT). Paris, France.
Université Paris Descartes. CNRS UMR 8147. Paris, Frrance.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Université Paris Descartes. CNRS UMR 8601. Chimie et Biologie, Nucléo(s)tides et Immunologie Thérapeutique (CBNIT). Paris, France.
Institut Pasteur. Unité des Interactions moléculaires Flavivirus-Hôtes. Paris, France
Universidade Federal do Mato Grosso do Sul. Faculdade de Medicina. Departamento de Clínica Medica. Campo Grande, MS, Brasil.
Centro de Referencia em Dengue.Campos de Goytacases, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Viral. Rio de Janeiro, RJ, Brasil.
Université Paris Descartes. CNRS UMR 8601. Chimie et Biologie, Nucléo(s)tides et Immunologie Thérapeutique (CBNIT). Paris, France.
Abstract
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.
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