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Autophagy is a cellular response against stresses which include the infection of viruses and bacteria. We unravel that Dengue virus-2 (DV2) can trigger autophagic process in various infected cell lines demonstrated by GFP-LC3 dot formation and increased LC3-II formation. Autophagosome formation was also observed under the transmission electron microscope. DV2-induced autophagy further enhances the titers of extracellular and intracellular viruses indicating that autophagy can promote viral replication in the infected cells. Moreover, our data show that ATG5 protein is required to execute DV2-induced autophagy. All together, we are the first to demonstrate that DV can activate autophagic machinery that is favorable for viral replication.

Vascular leakage, one hallmark of dengue haemorrhagic fever (DHF) and dengue shock syndrome, has been linked to the mediators secreted from cells in the circulatory system. In this study, extremely high expression levels of monocyte chemoattractant protein-1 (MCP-1) were found in the plasma of DHF patients compared with low MCP-1 expression levels in the plasma of enterovirus 71-infected patients. It was also found that MCP-1 expression was induced in dengue virus 2 (DV2)-infected monocytes and lymphocytes, but not in liver or endothelial cells. Exposing monolayers of human umbilical vein endothelial cells (HUVECs) to recombinant human MCP-1 (rhMCP-1) or to the culture supernatant of DV2-infected human monocytes increased the vascular permeability of the cells. MCP-1-neutralizing monoclonal antibody only partially prevented monolayer permeability change. Consistently, the distribution of the tight junction protein ZO-1 on the cellular membranes of HUVECs was disrupted by rhMCP-1 or by the conditioned medium of DV2-infected monocytes. In summary, it was found that the increased permeability and disrupted tight junctions of human vascular endothelium cells were effected through a mechanism partially dependent on MCP-1, which was secreted by DV2-infected monocytes and lymphocytes.

Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells. We demonstrate that PERK-eIF2α and IRE1α-JNK signaling pathways increased autophagy and viral load after DENV infection. However, ATF6-related pathway showed no effect on autophagy and viral replication. IRE1α-JNK downstream molecule Bcl-2 was phosphorylated by activated JNK and dissociated from Beclin 1, which playing a critical role in autophagy activation. These findings were confirmed as decreased viral titer, attenuated disease symptoms, and prolonged survival rate in the presence of JNK inhibitor in vivo. In summary, we are the first to reveal that DENV2-induced ER stress increases autophagy activity, DENV replication, and pathogenesis through two UPR signaling pathways both in vitro and in vivo.