The role of dengue virus infection induced ER stress and autophagy in Meg01 cell and in suckling mice pathogenesis

Abstract

Dengue virus (DENV) is an envelope virus with single-stranded positive RNA belonging to Flaviviridae Autophagy is a mechanism to maintain cell homeostasis by degrading components in the autolysosome Previous studies reported that DENV infection activates autophagy which is beneficial to viral replication Because Flaviviruses utilize endoplasmic reticulum (ER) for replication accumulated viral proteins on its surface induces ER stress and persistent ER stress leads to apoptosis Therefore cells trigger the unfolding protein response (UPR) to clean these unfolded proteins We previously revealed that one of the three UPR pathways IRE-1?->JNK->Bcl-2 signaling pathway could induce autophagy We found that inhibition of JNK pathway by a JNK phosphorylation inhibitor (SP600125) suppressed autophagy decreased dengue virus replication and alleviated disease symptoms In this study we further found that inhibition of IRE-1?->JNK->Bcl-2->BECN1-> autophagy signaling pathway by SP600125 not only decreased DENV2 replication but also alleviated disease symptoms and survival rate in mice Previous studies reported that DENV infects and propagates in platelet progenitor megakaryocytes DENV infection in megakaryocytes interferes with their differentiation and maturation which may lead to clinical thrombopenia in DENV patients Although megakaryocytes are reported to be the target cells for DENV infection the effect of DENV infection on megakaryocytes remains unclear In this study we revealed that DENV2 infection of Meg01 cells induces ER stress and a complete autophagy flux Differently DENV-induced autophagy in Meg01 cells decreased virus replication Previous studies suggest that secretory autophagy transports high mobility group box 1 (HMGB1) to the extracellular space in the acute inflammation phase DENV2 infection of Meg01 cells increased the intracellular and the extracellular levels of the proinflammatory cytokine HMGB1 We further found that in DENV2 infected Meg01 cells their size was increased multinuclei and chromosome abnormality Our findings in DENV2 infected Meg01 cells may be related to the symptoms of thrombopenia and bleeding tendency in severe dengue patients

Date of Award	2016 Feb 19
Original language	English
Supervisor	Hsiao-Sheng Liu (Supervisor)