Role of endoplasmic reticulum stress-related unfolded protein response and its implications in dengue virus infection for biomarker development

Dengue virus (DENV) causes debilitating disease in humans, which varies at different rates in host cells, such as monocytes, macrophages, dendritic cells, Langerhans cells, and other cell types. Such heterogeneity in DENV infection in cells could be attributed to a range of factors, including host cell immune response, anti-viral cellular proteins, and virus mediated cellular autophagy. This review delineates an important feature of every cell, the unfolded protein response (UPR) that is attributed to the accumulation of several viral and unfolded/misfolded proteins, such as in DENV infection. UPR is a normal process to counteract endoplasmic reticulum (ER) stress that leads to cell autophagy; though the phenomenon is markedly upregulated during DENV infection. This could be attributed to the uncontrolled activation of the key UPR signaling pathways: inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6), which promote cell autophagy under normal and diseased conditions through the downstream regulation of apoptosis promoting factors such as X-box binding protein (XBP1), GADD34, and ATF-6. Because DENV can modulate these signaling cascades, by promoting dysregulated cell autophagy, the ER stress mediated UPR pathways and the inherent agents could play an important role in delineating the severity of dengue infection with a potential for developing DENV targeted therapeutics.